Abstract
BACKGROUND
Maternal factors, including increasing childbearing age and various life-style factors, are associated with poorer short- and long-term outcomes for children, whereas knowledge of paternal parameters is limited. Recently, increasing paternal age has been associated with adverse obstetric outcomes, birth defects, autism spectrum disorders and schizophrenia in children.
OBJECTIVE AND RATIONALE
The aim of this systematic review is to describe the influence of paternal factors on adverse short- and long-term child outcomes.
SEARCH METHODS
PubMed, Embase and Cochrane databases up to January 2017 were searched. Paternal factors examined included paternal age and life-style factors such as body mass index (BMI), adiposity and cigarette smoking. The outcome variables assessed were short-term outcomes such as preterm birth, low birth weight, small for gestational age (SGA), stillbirth, birth defects and chromosomal anomalies. Long-term outcome variables included mortality, cancers, psychiatric diseases/disorders and metabolic diseases. The systematic review follows PRISMA guidelines. Relevant meta-analyses were performed.
OUTCOMES
The search included 14 371 articles out of which 238 met the inclusion criteria, and 81 were included in quantitative synthesis (meta-analyses). Paternal age and paternal life-style factors have an association with adverse outcome in offspring. This is particularly evident for psychiatric disorders such as autism, autism spectrum disorders and schizophrenia, but an association is also found with stillbirth, any birth defects, orofacial clefts and trisomy 21. Paternal height, but not BMI, is associated with birth weight in offspring while paternal BMI is associated with BMI, weight and/or body fat in childhood. Paternal smoking is found to be associated with an increase in SGA, birth defects such as congenital heart defects, and orofacial clefts, cancers, brain tumours and acute lymphoblastic leukaemia. These associations are significant although moderate in size, with most pooled estimates between 1.05 and 1.5, and none exceeding 2.0.
WIDER IMPLICATIONS
Although the increased risks of adverse outcome in offspring associated with paternal factors and identified in this report represent serious health effects, the magnitude of these effects seems modest.
Introduction
There is evidence that reproductive failures originate during the periconceptional period and that such failures are influenced by the age and the life-style of the partners (Sinclair and Watkins, 2013; Steegers-Theunissen et al., 2013). Maternal factors, such as the woman’s childbearing age and various life-style factors, are associated with poorer short- and long-term outcomes in the offspring (Jacobsson et al., 2004; Wennberg et al., 2016) whereas knowledge of the influence of paternal factors is limited (Soubry et al., 2014).
Over the last few decades, the childbearing age of the mother has increased worldwide from the early 20s to the early 30s (National Institute for Health and Welfare. Nordic perinatal statistics, 2014. Helsinki, Finland). This has increased the focus on the influence of maternal age on the short and long-term health of mothers and children (Jacobsson et al., 2004). However, there has been less focus on the age of the male partner, which has been rising in parallel with maternal childbearing age (Khandwala et al., 2017). Recently, paternal age has been associated with a wide range of adverse health effects in offspring, including both autism spectrum disorders (ASDs) and schizophrenia (Reichenberg et al., 2006). The mechanisms explaining these associations remain unclear (Frans et al., 2015). As a man ages, the number of de novo mutations in his sperm increases along with the chance that a child might carry a deleterious mutation leading to possible diseases (Kong et al., 2012). Recently, a novel mechanism has been suggested which may contribute to the association with paternal age, the process known as ‘selfish spermatogonial selection’ (Goriely and Wilkie, 2012) where rare spermatogonial cells bearing mutations are positively selected leading to their progressive clonal expansion. This process seems to affect all men, especially as they age.
Furthermore, advanced paternal age has been linked to aneuploidy in autosomes and sex-chromosomes (Lowe et al., 2001; Zhu et al., 2005b) and epigenetic alterations have been proposed as mechanisms by which modifications in gene expression can be transmitted to the offspring (Perrin et al., 2007). In addition, older fathers may represent a non-typical male population, as both higher and lower socio-economic statuses are overrepresented among older fathers (Nilsen et al., 2013).
Whereas, it is well known that maternal smoking, alcohol consumption and high BMI are associated with poorer short- and long-term outcomes for the children, knowledge of the effects of paternal life-style factors is limited. Malnutrition may impair several metabolic pathways (Steegers-Theunissen et al., 2013), and cigarette smoking can cause DNA or chromosomal damage in human germinal cells, including spermatozoa (Zenzes, 2000). Because ejaculated sperm has minimal, if any, repair capacity it is likely that these changes can be transmitted to the offspring.
The aim of this systematic review was to assess the influence of periconceptional paternal factors on adverse short and long-term child outcomes. These include preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), birth defects, chromosomal anomalies, psychiatric disorders such as schizophrenia and autism disorders, mortality, impaired neurodevelopment and cognitive functions, and cardio-metabolic functions. We have included the following paternal exposure factors: age, BMI, height, and/or weight and cigarette smoking.
Methods
We searched the PubMed, Cochrane and Embase databases up to January 2017. Exposures were periconceptional paternal age, paternal smoking and paternal BMI, height, and/or weight. Short-term obstetric outcomes we looked for included PTB, birth weight (BW), LBW, SGA, stillbirth and neonatal death (NND). Further significant outcomes were children with birth defects in general, and selected birth defects i.e. orofacial clefts, gastroschisis, congenital heart defects (CHDs), spina bifida and trisomy 21. Long-term outcomes included childhood mortality and morbidity e.g. leukaemia and other malignancies, childhood body weight and BMI, cardio-metabolic disorders, autism/ASD, schizophrenia, other psychiatric disorders and impaired cognitive function. Several of these outcomes when appropriate were used for meta-analysis.
Systematic search for evidence
The terms used in the searches are listed below:
(‘Paternal Age’[Mesh]) OR (‘Paternal Exposure’[Mesh]) AND (‘Congenital Abnormalities’)[Mesh] OR congenital malformat*[tiab] OR congenital abnormal*[tiab] OR birth defect*[tiab] OR ‘Birth Weight’[Mesh] OR birth weight[tiab] OR birth weight[tiab] OR premature birth[tiab] OR premature delivery[tiab] OR ‘Perinatal Mortality’[Mesh] OR ‘Perinatal Death’[Mesh] OR perinatal outcome*[tiab] OR ‘Stillbirth’[Mesh] OR ‘Live Birth’[Mesh] OR stillbirth[tiab] OR live birth*[tiab] OR outcome[tiab] OR outcomes[tiab] OR gestational age[tiab] OR children[tiab] OR child[tiab] OR ‘Autism Spectrum Disorder’[Mesh] OR ‘Autistic Disorder’[Mesh] OR ‘Schizophrenia’[Mesh] OR autism[tiab] OR autistic[tiab] OR schizophrenia[tiab]) NOT (animals[mh] AND humans[mh])) NOT (‘News’[Publication Type] OR ‘Newspaper Article’[Publication Type]).
We also manually searched reference lists of identified articles for additional references. Guidelines for meta-analysis and systematic reviews of observational studies were followed (Stroup et al., 2000). The literature search was performed by two researchers (C.B. and U.B.W.) and one librarian. Screening of abstracts and of full papers for inclusion was done by pairs of reviewers (C.B. and U.B.W., A.P. and A.L., N.O. and L.B.R., V.S.A. and H.L.). Differences of opinion in the team were solved by discussion until consensus was achieved.
Inclusion and exclusion of studies
Original studies published in English and the Nordic languages were included. In the case of double publication, the latest study was included. Studies with a control group and case series with more than 100 patients were included. Concerning very rare diseases, studies with fewer cases were also included. Studies published only as abstracts and case reports were excluded. Studies dealing with paternal age were excluded if they did not adjust for maternal age. Systematic reviews without meta-analyses were excluded.
Definitions
PTB was defined as gestational age <37 weeks, very PTB (VPTB) as a gestational age <32 weeks. LBW was defined as BW <2500 g and very LBW (VLBW) as a BW <1500 g. SGA/intrauterine growth retardation (IUGR), stillbirth and birth defects were defined by each author.
Appraisal of certainty of evidence
The methodological quality of the studies, in terms of risk of bias, was assessed by pairs of reviewers. We used the tools developed by SBU (Swedish Agency for Health Technology Assessment and Assessment of Social Services) (www.sbu.se/sv/Evidensbaserad-vard/Utvardering-av-metoder-i-halso-och-sjukvarden--En-handbok/) for assessing original articles, which grade articles as being of low, moderate and high quality. For systematic reviews we used AMSTAR (AMSTAR: Assessing the Methodological Quality of Systematic Reviews Systematic reviews, cohort and case control studies, but not case series, were assessed for methodological quality. For certainty of evidence we used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (Guyatt et al., 2008).
The GRADE system evaluates the following variables for all studies, both combined and per outcome: Design, study limitations, consistency, directness, precision, publication bias, magnitude of effect, relative effect and absolute effect. Certainty levels are divided into high, moderate, low and very low certainty. Certainty levels are based on our confidence in the effect estimate, which in turn is based on the number of studies, design of studies, consistency of associations between studies, study limitations, directness, precision, publication bias, effect size, and relative and absolute effect.
The certainty levels are; very confident = high certainty, moderately confident = moderate certainty, limited confidence = low certainty and very little confidence = very low certainty. If conclusions are based on RCTs, GRADE starts at high certainty level (level 4) but can be downgraded, while if conclusions are based on observational studies GRADE starts at low certainty level (level 2) but might be upgraded (or downgraded). If conclusions were based on case series, no assessment of GRADE was performed.
Statistics
Outcomes are given in odds ratio (OR), adjusted odds ratio (AOR), adjusted prevalence odds ratio (APOR), hazard ratio (HR), adjusted hazard ratio (AHR), RR (relative risk), adjusted relative risk, adjusted prevalence ratio (APR), adjusted incidence rate ratio (AIRR) or adjusted mortality rate ratio (AMRR) with 95% CI. A few studies used mean standardized BW and standardized regression coefficient (Beta).
Meta-analyses were performed despite significant heterogeneity in reference groups for paternal age and despite the fact that outcomes were given in AOR, AHR or APR. A random effects meta-analysis using the DerSimonian and Laird method, with the estimate of heterogeneity being taken from the Mantel-Haenszel model, was used in the analysis (command metan in Stata 15: StataCorp LLC, TX, USA).
Results
The search strategy identified a total of 14 371 articles, of which 238 were selected for inclusion in the systematic review and 81 for inclusion in quantitative synthesis (meta-analysis) (Fig. 1, PRISMA Flow chart)
Figure 1
PRISMA flow diagram for a systematic review and meta-analysis on the effect of paternal factors on perinatal and paediatric outcomes.
Among the studies included were 10 meta-analyses, 127 cohort studies, 96 case control studies and 5 case series (Supplementary Tables SI–III). Excluded studies, with reasons for exclusion, are presented in Supplementary Table SIV.
A quality assessment of the cohort and case control studies included is presented in Supplementary Tables SV–VII and for systematic reviews in Supplementary Table SVIII. Of the selected cohort and case control studies, 35 articles were of high quality, 103 were of moderate quality and 85 of low quality. Of the systematic reviews included, nine were of medium quality and one was of low quality.
Paternal age at childbirth and short-term outcomes for offspring
Obstetric outcomes
PTB and very PTB
Nine cohort studies, comprising more than 10 million births in total, reported on PTB or VPTB or both (Supplementary Table SI, Table I). Six cohort studies were of high quality and three of medium quality. Three studies (Abel et al., 2002; Zhu et al., 2005a; Astolfi et al., 2006) found a small but significantly increased risk of PTB associated with advanced paternal age. Low paternal age (<20 or <25 years) was associated with a higher risk of PTB in four studies (Abel et al., 2002; Chen et al., 2008; Alio et al., 2012; Astolfi et al., 2006). Our meta-analysis including eight of the studies showed a pooled AOR estimate of 1.02 (95% CI 1.00–1.05) of PTB in older versus younger (reference groups varied between 20 and 34 years) fathers (the forest plot is shown in Fig. 2). In the Danish study by Zhu et al. (2005a) the risk of VPTB in older fathers was increased, but not in the US study by Basso and Wilcox (2006).
Table IStudies on human paternal age and obstetric outcomes identified in a systematic review of the literature on the effect of paternal factors on perinatal and paediatric outcomes.
Author, year, country
. | Study design
. | Number of pregnancies, births or children
. | Result
. | Outcomes Comments Adjustments
. | Study quality
. |
---|
Outcomes (risk estimates)
. | Reference group/controls
. |
---|
Original articles n = 16 |
Abel et al. (2002), USA | Cohort study | 155 903 births | Paternal age < 20 years: PTB: AOR 1.24 (1.02–1.52) LBW: AOR 1.28 (1.02–1.61)
| Paternal age 21–25 years | PTB and LBW: Significantly higher risk for low paternal age. No other significances. Adjusted for maternal age, socio-economic status, infant gender and race
| High |
Alio et al. (2012), USA | Cohort study | 755 334 singletons | LBW, PTB (33–37 weeks), VPTB (<33 weeks): Paternal age < 20, 20–24 years: AORs 1.10 to 1.31 (1.07 to 1.41)* >45 years: AORs 1.13 to 1.19 (1.05 to 1.44)* SGA: <20 years: AORs 1.18 (1.13–1.24) 20–24 years: 1.12 (1.10–1.15) Stillbirth (≥20 weeks): 40–45 years: AOR 1.24 (1.04–1.47) >45 years: 1.33 (1.02–1.77) *lowest and highest 95% CI
| Paternal age 25–29 years | LBW, PTB, VPTB: U-shaped risk with significantly higher risk for low and high paternal age. SGA: Significantly higher risk for younger fathers. Stillbirth: Significantly higher risk for older fathers. Adjusted for maternal age, race, education, marital status, years of birth, maternal complications, prenatal care, smoking and alcohol
| High |
Astolfi et al. (2004), Italy | Cohort study | 3 619 647 births | Stillbirth: Paternal age ≥ 40 years, maternal age <35 years, high education OR 1.12 (1.00–1.25) Paternal age ≥40 years, maternal age <35 years, low education: OR 1.29 (1.17–1.43)
| Paternal age <40 years, maternal age <35 years | | High |
Astolfi et al. (2006), Italy | Cohort study | 1 510 893 births | Paternal age <25 years: PTB: OR 1.19 (1.12–1.26) VPTB: 1.36 (1.19–1.56) PTB: 35–39, 40–44, 45–49 years ORs 1.01 to 1.36 (1.08 to 1.56)* VPTB: 35–39, 40–44, 45–49 years ORs 1.16 to 1.72 (1.06 to 2.36)* *lowest and highest 95% CI
| Paternal age 25–29 years, maternal age 25–29 years | | High |
Basso and Wilcox (2006), Denmark | Cohort study | 2 499 633 live singletons | VPTB: Paternal age 30–34, 35–39, 40–44, 45–49 years: AORs 0.86 to 1.11 (0.47 to 1.55)* Highest AOR among fathers ≥50 years 1.3 (0.6–2.8) among women 20–24 years *lowest and highest 95% CI
| Paternal age 25–29 years, maternal age 25–29 years | No increase in VPTB by paternal age. Stratified for maternal age (20–24, 25–29, 30–34 years), adjusted for mother’s education and smoking | High |
Chen et al. (2008), USA | Cohort study | 2 614 966 singletons | Paternal age <20 years: PTB, VPTB, LBW, SGA, NND, low Apgar score: AORs 1.13 to 1.22 (1.01 to 1.49)* *lowest and highest 95% CI
| Paternal age 20–29 years | PTB, VPTB, LBW, SGA, NND, low Apgar score: Significantly higher risk for young age. For high age no significantly increased age up to >50 years. Adjusted for paternal race, maternal age, educational level, smoking, alcohol, prenatal care and infant gender
| High |
Iwayama et al. (2011), Japan | Cohort study | 55 005/73 993 infants selected at 1 month and 17 263/73 993 at 12 month healthy baby check-up, 3588 underwent both 1 and 12 months check-up | BW increased with paternal age for non-firstborn infants (P = 0.0004) and LBW decreased with paternal age for non-firstborn infants (P = 0.0022) | Paternal age was categorized: <20, 20–29, 30–39, 40–49 and ≥50 years. The younger category group was the reference group. | | Low |
Nybo Andersen et al. (2004), Denmark | Cohort study | 23 821 pregnancies | | Paternal age 25–29 years | Stillbirth: Significantly higher high for older fathers. Adjustment for maternal age, reproductive history and maternal life style during pregnancy. Not included in meta-analysis, due to overlap with Urhoj et al. (2017a)
| Medium |
Olshan et al. (1995), USA | Cohort study | 254 892 singletons | No increase in PTB, LBW and SGA by paternal age | Paternal age 25–29 years | PTB, LBW, SGA: Adjusted for maternal age, race, gravidity, smoking, marital status, education and infant gender
| Medium |
Reichman and Teitler (2006), USA | Cohort study | 4621 singletons | Paternal age >34 years: LBW: AOR 1.7 (1.3–2.2)
| Paternal age 20–34 years | LBW: Significantly increased for older fathers. Adjusted for maternal age, gender, mother’s birth place, parity, marital status and health insurance status.
| Medium/low |
Selvin and Garfinkel (1972), USA | Cohort study | 1 515 433 singletons | U-shaped relation with slightly higher rates of LBW at young and older paternal ages | No | | Low |
Stern et al. (2014), USA | Cohort study | | Fertile group: Paternal age 35–40, 41–45, ≥46 years: No association with paternal age and PTB, LBW or SGA
| Paternal age ≤34 years, maternal age ≤34 years | PTB, LBW, SGA: Adjusted for parental race and ethnicity, parental education, diabetes, chronic hypertension. Stratified for maternal age, ≤34 and 35–40 years.
| Medium |
Tough et al. (2003), Canada | Cohort study | 283 956 births | Paternal age 20–24, 25–29, 30–34. 35–39, 40–44 years: Significantly decreased risk of LBW: AORs 0.76 to 0.84 (0.67 to 0.95)* PTB: AORs 0.75 to 0.87 (0.66 to 0.97)* * lowest and highest 95% CI
| Paternal age ≤19 years | LBW, PTB: Reference group inadequate. Adjusted for maternal age. | Medium |
Urhoj et al. (2017a), Denmark | Cohort study | 944 031 pregnancies with gestational age ≥22 weeks, 4946 stillbirths | Paternal age 35–39, 40–44 and ≥50 years: Stillbirth: AHRs 1.16 to 1.58 (1.07 to 2.11)* * lowest and highest 95% CI
| Paternal age 30–34 years | Stillbirth: Paternal age associated with the risk of stillbirth in a J-shaped manner with the highest adjusted HRs among fathers >50 years. Adjusted for maternal age in 1 year categories, year of birth: 1994–1999, 2000–2005, 2006–2010, parental education, in sensitivity analysis also for ethnicity, maternal reproductive history
| High |
Zakar et al. (2015), Pakistan | Cohort study | 5724 births | Paternal age (15–24 years or ≥40 years) was not associated with ‘small size at birth’ (SSB) or NND | Paternal age 25–39 years | | Low |
Zhu et al. (2005a), Denmark | Cohort study | 70 347 singletons | PTB: 35–39 years: AOR 1.1 (1.0–1.3) 40–44 years: AOR 1.2 (1.0–1.4) VPTB: 35–39 years: AOR 1.4 (1.0–2.0) 40–44 years: AOR 1.7 (1.1–2.6)
| Paternal age 20–24 years | PTB, VPTB: Risk of PTB, mainly VPTB increased with paternal age Adjusted maternal age, parity, paternal education and income, calendar year and infant gender
| High |
Author, year, country
. | Study design
. | Number of pregnancies, births or children
. | Result
. | Outcomes Comments Adjustments
. | Study quality
. |
---|
Outcomes (risk estimates)
. | Reference group/controls
. |
---|
Original articles n = 16 |
Abel et al. (2002), USA | Cohort study | 155 903 births | Paternal age < 20 years: PTB: AOR 1.24 (1.02–1.52) LBW: AOR 1.28 (1.02–1.61)
| Paternal age 21–25 years | PTB and LBW: Significantly higher risk for low paternal age. No other significances. Adjusted for maternal age, socio-economic status, infant gender and race
| High |
Alio et al. (2012), USA | Cohort study | 755 334 singletons | LBW, PTB (33–37 weeks), VPTB (<33 weeks): Paternal age < 20, 20–24 years: AORs 1.10 to 1.31 (1.07 to 1.41)* >45 years: AORs 1.13 to 1.19 (1.05 to 1.44)* SGA: <20 years: AORs 1.18 (1.13–1.24) 20–24 years: 1.12 (1.10–1.15) Stillbirth (≥20 weeks): 40–45 years: AOR 1.24 (1.04–1.47) >45 years: 1.33 (1.02–1.77) *lowest and highest 95% CI
| Paternal age 25–29 years | LBW, PTB, VPTB: U-shaped risk with significantly higher risk for low and high paternal age. SGA: Significantly higher risk for younger fathers. Stillbirth: Significantly higher risk for older fathers. Adjusted for maternal age, race, education, marital status, years of birth, maternal complications, prenatal care, smoking and alcohol
| High |
Astolfi et al. (2004), Italy | Cohort study | 3 619 647 births | Stillbirth: Paternal age ≥ 40 years, maternal age <35 years, high education OR 1.12 (1.00–1.25) Paternal age ≥40 years, maternal age <35 years, low education: OR 1.29 (1.17–1.43)
| Paternal age <40 years, maternal age <35 years | | High |
Astolfi et al. (2006), Italy | Cohort study | 1 510 893 births | Paternal age <25 years: PTB: OR 1.19 (1.12–1.26) VPTB: 1.36 (1.19–1.56) PTB: 35–39, 40–44, 45–49 years ORs 1.01 to 1.36 (1.08 to 1.56)* VPTB: 35–39, 40–44, 45–49 years ORs 1.16 to 1.72 (1.06 to 2.36)* *lowest and highest 95% CI
| Paternal age 25–29 years, maternal age 25–29 years | | High |
Basso and Wilcox (2006), Denmark | Cohort study | 2 499 633 live singletons | VPTB: Paternal age 30–34, 35–39, 40–44, 45–49 years: AORs 0.86 to 1.11 (0.47 to 1.55)* Highest AOR among fathers ≥50 years 1.3 (0.6–2.8) among women 20–24 years *lowest and highest 95% CI
| Paternal age 25–29 years, maternal age 25–29 years | No increase in VPTB by paternal age. Stratified for maternal age (20–24, 25–29, 30–34 years), adjusted for mother’s education and smoking | High |
Chen et al. (2008), USA | Cohort study | 2 614 966 singletons | Paternal age <20 years: PTB, VPTB, LBW, SGA, NND, low Apgar score: AORs 1.13 to 1.22 (1.01 to 1.49)* *lowest and highest 95% CI
| Paternal age 20–29 years | PTB, VPTB, LBW, SGA, NND, low Apgar score: Significantly higher risk for young age. For high age no significantly increased age up to >50 years. Adjusted for paternal race, maternal age, educational level, smoking, alcohol, prenatal care and infant gender
| High |
Iwayama et al. (2011), Japan | Cohort study | 55 005/73 993 infants selected at 1 month and 17 263/73 993 at 12 month healthy baby check-up, 3588 underwent both 1 and 12 months check-up | BW increased with paternal age for non-firstborn infants (P = 0.0004) and LBW decreased with paternal age for non-firstborn infants (P = 0.0022) | Paternal age was categorized: <20, 20–29, 30–39, 40–49 and ≥50 years. The younger category group was the reference group. | | Low |
Nybo Andersen et al. (2004), Denmark | Cohort study | 23 821 pregnancies | | Paternal age 25–29 years | Stillbirth: Significantly higher high for older fathers. Adjustment for maternal age, reproductive history and maternal life style during pregnancy. Not included in meta-analysis, due to overlap with Urhoj et al. (2017a)
| Medium |
Olshan et al. (1995), USA | Cohort study | 254 892 singletons | No increase in PTB, LBW and SGA by paternal age | Paternal age 25–29 years | PTB, LBW, SGA: Adjusted for maternal age, race, gravidity, smoking, marital status, education and infant gender
| Medium |
Reichman and Teitler (2006), USA | Cohort study | 4621 singletons | Paternal age >34 years: LBW: AOR 1.7 (1.3–2.2)
| Paternal age 20–34 years | LBW: Significantly increased for older fathers. Adjusted for maternal age, gender, mother’s birth place, parity, marital status and health insurance status.
| Medium/low |
Selvin and Garfinkel (1972), USA | Cohort study | 1 515 433 singletons | U-shaped relation with slightly higher rates of LBW at young and older paternal ages | No | | Low |
Stern et al. (2014), USA | Cohort study | | Fertile group: Paternal age 35–40, 41–45, ≥46 years: No association with paternal age and PTB, LBW or SGA
| Paternal age ≤34 years, maternal age ≤34 years | PTB, LBW, SGA: Adjusted for parental race and ethnicity, parental education, diabetes, chronic hypertension. Stratified for maternal age, ≤34 and 35–40 years.
| Medium |
Tough et al. (2003), Canada | Cohort study | 283 956 births | Paternal age 20–24, 25–29, 30–34. 35–39, 40–44 years: Significantly decreased risk of LBW: AORs 0.76 to 0.84 (0.67 to 0.95)* PTB: AORs 0.75 to 0.87 (0.66 to 0.97)* * lowest and highest 95% CI
| Paternal age ≤19 years | LBW, PTB: Reference group inadequate. Adjusted for maternal age. | Medium |
Urhoj et al. (2017a), Denmark | Cohort study | 944 031 pregnancies with gestational age ≥22 weeks, 4946 stillbirths | Paternal age 35–39, 40–44 and ≥50 years: Stillbirth: AHRs 1.16 to 1.58 (1.07 to 2.11)* * lowest and highest 95% CI
| Paternal age 30–34 years | Stillbirth: Paternal age associated with the risk of stillbirth in a J-shaped manner with the highest adjusted HRs among fathers >50 years. Adjusted for maternal age in 1 year categories, year of birth: 1994–1999, 2000–2005, 2006–2010, parental education, in sensitivity analysis also for ethnicity, maternal reproductive history
| High |
Zakar et al. (2015), Pakistan | Cohort study | 5724 births | Paternal age (15–24 years or ≥40 years) was not associated with ‘small size at birth’ (SSB) or NND | Paternal age 25–39 years | | Low |
Zhu et al. (2005a), Denmark | Cohort study | 70 347 singletons | PTB: 35–39 years: AOR 1.1 (1.0–1.3) 40–44 years: AOR 1.2 (1.0–1.4) VPTB: 35–39 years: AOR 1.4 (1.0–2.0) 40–44 years: AOR 1.7 (1.1–2.6)
| Paternal age 20–24 years | PTB, VPTB: Risk of PTB, mainly VPTB increased with paternal age Adjusted maternal age, parity, paternal education and income, calendar year and infant gender
| High |
Table IStudies on human paternal age and obstetric outcomes identified in a systematic review of the literature on the effect of paternal factors on perinatal and paediatric outcomes.
Author, year, country
. | Study design
. | Number of pregnancies, births or children
. | Result
. | Outcomes Comments Adjustments
. | Study quality
. |
---|
Outcomes (risk estimates)
. | Reference group/controls
. |
---|
Original articles n = 16 |
Abel et al. (2002), USA | Cohort study | 155 903 births | Paternal age < 20 years: PTB: AOR 1.24 (1.02–1.52) LBW: AOR 1.28 (1.02–1.61)
| Paternal age 21–25 years | PTB and LBW: Significantly higher risk for low paternal age. No other significances. Adjusted for maternal age, socio-economic status, infant gender and race
| High |
Alio et al. (2012), USA | Cohort study | 755 334 singletons | LBW, PTB (33–37 weeks), VPTB (<33 weeks): Paternal age < 20, 20–24 years: AORs 1.10 to 1.31 (1.07 to 1.41)* >45 years: AORs 1.13 to 1.19 (1.05 to 1.44)* SGA: <20 years: AORs 1.18 (1.13–1.24) 20–24 years: 1.12 (1.10–1.15) Stillbirth (≥20 weeks): 40–45 years: AOR 1.24 (1.04–1.47) >45 years: 1.33 (1.02–1.77) *lowest and highest 95% CI
| Paternal age 25–29 years | LBW, PTB, VPTB: U-shaped risk with significantly higher risk for low and high paternal age. SGA: Significantly higher risk for younger fathers. Stillbirth: Significantly higher risk for older fathers. Adjusted for maternal age, race, education, marital status, years of birth, maternal complications, prenatal care, smoking and alcohol
| High |
Astolfi et al. (2004), Italy | Cohort study | 3 619 647 births | Stillbirth: Paternal age ≥ 40 years, maternal age <35 years, high education OR 1.12 (1.00–1.25) Paternal age ≥40 years, maternal age <35 years, low education: OR 1.29 (1.17–1.43)
| Paternal age <40 years, maternal age <35 years | | High |
Astolfi et al. (2006), Italy | Cohort study | 1 510 893 births | Paternal age <25 years: PTB: OR 1.19 (1.12–1.26) VPTB: 1.36 (1.19–1.56) PTB: 35–39, 40–44, 45–49 years ORs 1.01 to 1.36 (1.08 to 1.56)* VPTB: 35–39, 40–44, 45–49 years ORs 1.16 to 1.72 (1.06 to 2.36)* *lowest and highest 95% CI
| Paternal age 25–29 years, maternal age 25–29 years | | High |
Basso and Wilcox (2006), Denmark | Cohort study | 2 499 633 live singletons | VPTB: Paternal age 30–34, 35–39, 40–44, 45–49 years: AORs 0.86 to 1.11 (0.47 to 1.55)* Highest AOR among fathers ≥50 years 1.3 (0.6–2.8) among women 20–24 years *lowest and highest 95% CI
| Paternal age 25–29 years, maternal age 25–29 years | No increase in VPTB by paternal age. Stratified for maternal age (20–24, 25–29, 30–34 years), adjusted for mother’s education and smoking | High |
Chen et al. (2008), USA | Cohort study | 2 614 966 singletons | Paternal age <20 years: PTB, VPTB, LBW, SGA, NND, low Apgar score: AORs 1.13 to 1.22 (1.01 to 1.49)* *lowest and highest 95% CI
| Paternal age 20–29 years | PTB, VPTB, LBW, SGA, NND, low Apgar score: Significantly higher risk for young age. For high age no significantly increased age up to >50 years. Adjusted for paternal race, maternal age, educational level, smoking, alcohol, prenatal care and infant gender
| High |
Iwayama et al. (2011), Japan | Cohort study | 55 005/73 993 infants selected at 1 month and 17 263/73 993 at 12 month healthy baby check-up, 3588 underwent both 1 and 12 months check-up | BW increased with paternal age for non-firstborn infants (P = 0.0004) and LBW decreased with paternal age for non-firstborn infants (P = 0.0022) | Paternal age was categorized: <20, 20–29, 30–39, 40–49 and ≥50 years. The younger category group was the reference group. | | Low |
Nybo Andersen et al. (2004), Denmark | Cohort study | 23 821 pregnancies | | Paternal age 25–29 years | Stillbirth: Significantly higher high for older fathers. Adjustment for maternal age, reproductive history and maternal life style during pregnancy. Not included in meta-analysis, due to overlap with Urhoj et al. (2017a)
| Medium |
Olshan et al. (1995), USA | Cohort study | 254 892 singletons | No increase in PTB, LBW and SGA by paternal age | Paternal age 25–29 years | PTB, LBW, SGA: Adjusted for maternal age, race, gravidity, smoking, marital status, education and infant gender
| Medium |
Reichman and Teitler (2006), USA | Cohort study | 4621 singletons | Paternal age >34 years: LBW: AOR 1.7 (1.3–2.2)
| Paternal age 20–34 years | LBW: Significantly increased for older fathers. Adjusted for maternal age, gender, mother’s birth place, parity, marital status and health insurance status.
| Medium/low |
Selvin and Garfinkel (1972), USA | Cohort study | 1 515 433 singletons | U-shaped relation with slightly higher rates of LBW at young and older paternal ages | No | | Low |
Stern et al. (2014), USA | Cohort study | | Fertile group: Paternal age 35–40, 41–45, ≥46 years: No association with paternal age and PTB, LBW or SGA
| Paternal age ≤34 years, maternal age ≤34 years | PTB, LBW, SGA: Adjusted for parental race and ethnicity, parental education, diabetes, chronic hypertension. Stratified for maternal age, ≤34 and 35–40 years.
| Medium |
Tough et al. (2003), Canada | Cohort study | 283 956 births | Paternal age 20–24, 25–29, 30–34. 35–39, 40–44 years: Significantly decreased risk of LBW: AORs 0.76 to 0.84 (0.67 to 0.95)* PTB: AORs 0.75 to 0.87 (0.66 to 0.97)* * lowest and highest 95% CI
| Paternal age ≤19 years | LBW, PTB: Reference group inadequate. Adjusted for maternal age. | Medium |
Urhoj et al. (2017a), Denmark | Cohort study | 944 031 pregnancies with gestational age ≥22 weeks, 4946 stillbirths | Paternal age 35–39, 40–44 and ≥50 years: Stillbirth: AHRs 1.16 to 1.58 (1.07 to 2.11)* * lowest and highest 95% CI
| Paternal age 30–34 years | Stillbirth: Paternal age associated with the risk of stillbirth in a J-shaped manner with the highest adjusted HRs among fathers >50 years. Adjusted for maternal age in 1 year categories, year of birth: 1994–1999, 2000–2005, 2006–2010, parental education, in sensitivity analysis also for ethnicity, maternal reproductive history
| High |
Zakar et al. (2015), Pakistan | Cohort study | 5724 births | Paternal age (15–24 years or ≥40 years) was not associated with ‘small size at birth’ (SSB) or NND | Paternal age 25–39 years | | Low |
Zhu et al. (2005a), Denmark | Cohort study | 70 347 singletons | PTB: 35–39 years: AOR 1.1 (1.0–1.3) 40–44 years: AOR 1.2 (1.0–1.4) VPTB: 35–39 years: AOR 1.4 (1.0–2.0) 40–44 years: AOR 1.7 (1.1–2.6)
| Paternal age 20–24 years | PTB, VPTB: Risk of PTB, mainly VPTB increased with paternal age Adjusted maternal age, parity, paternal education and income, calendar year and infant gender
| High |
Author, year, country
. | Study design
. | Number of pregnancies, births or children
. | Result
. | Outcomes Comments Adjustments
. | Study quality
. |
---|
Outcomes (risk estimates)
. | Reference group/controls
. |
---|
Original articles n = 16 |
Abel et al. (2002), USA | Cohort study | 155 903 births | Paternal age < 20 years: PTB: AOR 1.24 (1.02–1.52) LBW: AOR 1.28 (1.02–1.61)
| Paternal age 21–25 years | PTB and LBW: Significantly higher risk for low paternal age. No other significances. Adjusted for maternal age, socio-economic status, infant gender and race
| High |
Alio et al. (2012), USA | Cohort study | 755 334 singletons | LBW, PTB (33–37 weeks), VPTB (<33 weeks): Paternal age < 20, 20–24 years: AORs 1.10 to 1.31 (1.07 to 1.41)* >45 years: AORs 1.13 to 1.19 (1.05 to 1.44)* SGA: <20 years: AORs 1.18 (1.13–1.24) 20–24 years: 1.12 (1.10–1.15) Stillbirth (≥20 weeks): 40–45 years: AOR 1.24 (1.04–1.47) >45 years: 1.33 (1.02–1.77) *lowest and highest 95% CI
| Paternal age 25–29 years | LBW, PTB, VPTB: U-shaped risk with significantly higher risk for low and high paternal age. SGA: Significantly higher risk for younger fathers. Stillbirth: Significantly higher risk for older fathers. Adjusted for maternal age, race, education, marital status, years of birth, maternal complications, prenatal care, smoking and alcohol
| High |
Astolfi et al. (2004), Italy | Cohort study | 3 619 647 births | Stillbirth: Paternal age ≥ 40 years, maternal age <35 years, high education OR 1.12 (1.00–1.25) Paternal age ≥40 years, maternal age <35 years, low education: OR 1.29 (1.17–1.43)
| Paternal age <40 years, maternal age <35 years | | High |
Astolfi et al. (2006), Italy | Cohort study | 1 510 893 births | Paternal age <25 years: PTB: OR 1.19 (1.12–1.26) VPTB: 1.36 (1.19–1.56) PTB: 35–39, 40–44, 45–49 years ORs 1.01 to 1.36 (1.08 to 1.56)* VPTB: 35–39, 40–44, 45–49 years ORs 1.16 to 1.72 (1.06 to 2.36)* *lowest and highest 95% CI
| Paternal age 25–29 years, maternal age 25–29 years | | High |
Basso and Wilcox (2006), Denmark | Cohort study | 2 499 633 live singletons | VPTB: Paternal age 30–34, 35–39, 40–44, 45–49 years: AORs 0.86 to 1.11 (0.47 to 1.55)* Highest AOR among fathers ≥50 years 1.3 (0.6–2.8) among women 20–24 years *lowest and highest 95% CI
| Paternal age 25–29 years, maternal age 25–29 years | No increase in VPTB by paternal age. Stratified for maternal age (20–24, 25–29, 30–34 years), adjusted for mother’s education and smoking | High |
Chen et al. (2008), USA | Cohort study | 2 614 966 singletons | Paternal age <20 years: PTB, VPTB, LBW, SGA, NND, low Apgar score: AORs 1.13 to 1.22 (1.01 to 1.49)* *lowest and highest 95% CI
| Paternal age 20–29 years | PTB, VPTB, LBW, SGA, NND, low Apgar score: Significantly higher risk for young age. For high age no significantly increased age up to >50 years. Adjusted for paternal race, maternal age, educational level, smoking, alcohol, prenatal care and infant gender
| High |
Iwayama et al. (2011), Japan | Cohort study | 55 005/73 993 infants selected at 1 month and 17 263/73 993 at 12 month healthy baby check-up, 3588 underwent both 1 and 12 months check-up | BW increased with paternal age for non-firstborn infants (P = 0.0004) and LBW decreased with paternal age for non-firstborn infants (P = 0.0022) | Paternal age was categorized: <20, 20–29, 30–39, 40–49 and ≥50 years. The younger category group was the reference group. | | Low |
Nybo Andersen et al. (2004), Denmark | Cohort study | 23 821 pregnancies | | Paternal age 25–29 years | Stillbirth: Significantly higher high for older fathers. Adjustment for maternal age, reproductive history and maternal life style during pregnancy. Not included in meta-analysis, due to overlap with Urhoj et al. (2017a)
| Medium |
Olshan et al. (1995), USA | Cohort study | 254 892 singletons | No increase in PTB, LBW and SGA by paternal age | Paternal age 25–29 years | PTB, LBW, SGA: Adjusted for maternal age, race, gravidity, smoking, marital status, education and infant gender
| Medium |
Reichman and Teitler (2006), USA | Cohort study | 4621 singletons | Paternal age >34 years: LBW: AOR 1.7 (1.3–2.2)
| Paternal age 20–34 years | LBW: Significantly increased for older fathers. Adjusted for maternal age, gender, mother’s birth place, parity, marital status and health insurance status.
| Medium/low |
Selvin and Garfinkel (1972), USA | Cohort study | 1 515 433 singletons | U-shaped relation with slightly higher rates of LBW at young and older paternal ages | No | | Low |
Stern et al. (2014), USA | Cohort study | | Fertile group: Paternal age 35–40, 41–45, ≥46 years: No association with paternal age and PTB, LBW or SGA
| Paternal age ≤34 years, maternal age ≤34 years | PTB, LBW, SGA: Adjusted for parental race and ethnicity, parental education, diabetes, chronic hypertension. Stratified for maternal age, ≤34 and 35–40 years.
| Medium |
Tough et al. (2003), Canada | Cohort study | 283 956 births | Paternal age 20–24, 25–29, 30–34. 35–39, 40–44 years: Significantly decreased risk of LBW: AORs 0.76 to 0.84 (0.67 to 0.95)* PTB: AORs 0.75 to 0.87 (0.66 to 0.97)* * lowest and highest 95% CI
| Paternal age ≤19 years | LBW, PTB: Reference group inadequate. Adjusted for maternal age. | Medium |
Urhoj et al. (2017a), Denmark | Cohort study | 944 031 pregnancies with gestational age ≥22 weeks, 4946 stillbirths | Paternal age 35–39, 40–44 and ≥50 years: Stillbirth: AHRs 1.16 to 1.58 (1.07 to 2.11)* * lowest and highest 95% CI
| Paternal age 30–34 years | Stillbirth: Paternal age associated with the risk of stillbirth in a J-shaped manner with the highest adjusted HRs among fathers >50 years. Adjusted for maternal age in 1 year categories, year of birth: 1994–1999, 2000–2005, 2006–2010, parental education, in sensitivity analysis also for ethnicity, maternal reproductive history
| High |
Zakar et al. (2015), Pakistan | Cohort study | 5724 births | Paternal age (15–24 years or ≥40 years) was not associated with ‘small size at birth’ (SSB) or NND | Paternal age 25–39 years | | Low |
Zhu et al. (2005a), Denmark | Cohort study | 70 347 singletons | PTB: 35–39 years: AOR 1.1 (1.0–1.3) 40–44 years: AOR 1.2 (1.0–1.4) VPTB: 35–39 years: AOR 1.4 (1.0–2.0) 40–44 years: AOR 1.7 (1.1–2.6)
| Paternal age 20–24 years | PTB, VPTB: Risk of PTB, mainly VPTB increased with paternal age Adjusted maternal age, parity, paternal education and income, calendar year and infant gender
| High |
Figure 2
Forest plot describing the association between paternal age and risk for PTB. AOR, adjusted odds ratios.
Conclusion: There may be little or no difference in the rate of PTB between older and younger fathers. Low certainty of evidence (GRADE⊕⊕○○).
Low BW and very low BW
Nine cohort studies (three high, three medium and three low quality) comprising almost 6 million births assessed LBW, two of them also VLBW (Abel et al., 2002: Chen et al., 2008) (Supplementary Table SI, Table I).
We performed a meta-analysis with LBW as outcome. We included six studies, and found a pooled estimate of 1.00 (95% CI 0.97–1.03) for LBW in older versus younger (reference groups varied between 20 and 34 years) fathers (Fig. 3). Low paternal age (<20 or <25 years) was associated with a higher risk of LBW in three studies (Abel et al., 2002; Chen et al., 2008; Alio et al., 2012).
Figure 3
Forest plot describing the association between paternal age and risk for LBW in offspring.
None of the studies assessing the risk of VLBW in older fathers found an increased risk.
Conclusion: There may be little or no difference in the rate of LBW between older and younger fathers. Low certainty of evidence (GRADE⊕⊕○○).
Small for gestational age
Five cohort studies (two high, two medium and one low quality), comprising almost 4 million births, found no association between infants born SGA and increased paternal age (Supplementary Table SI, Table I).
Conclusion: There may be little or no difference in the rate of SGA between older and younger fathers. Low certainty of evidence (GRADE⊕⊕○○).
Stillbirth/neonatal mortality
Four cohort studies, comprising between 23 821 and 3 610 647 births, three of high quality and one of medium quality, reported stillbirths (Supplementary Table SI, Table I. In an analysis of more than 3 million births, Astolfi et al. (2004) (high quality) found in an Italian cohort study a significantly increased risk of stillbirth when fathers were 40 or more, compared with fathers below 40 years of age. Alio et al. (2012) also found a significantly increased risk of stillbirth (more than 700,000 US births) for fathers more than 40 years old, when compared to fathers between 25 and 29 years after adjustment for multiple confounders. Two Danish studies with partial overlap (Nybo Andersen et al., 2004 ~24 000 births and Urhoj et al., 2017a almost 1 million births) found significantly increased risks for the offspring of fathers of 50 years or more (Nybo Andersen HR 3.9, reference group 25–29 years and Urhoj HR 1.58, reference group 30–34 years) (Nybo Andersen et al., 2004; Urhoj et al., 2017a). Our meta-analysis, including three studies, showed a higher risk of stillbirth for the children of older than younger fathers (reference groups varied between 20 and 40 years) with a pooled estimate of 1.19 (95% CI 1.10–1.30) (Fig. 4). Two cohort studies reported on NND; one of high quality (Chen et al., 2008) and one of low quality (Zakar et al., 2015). No increased risk of NND was found.
Figure 4
Forest plot describing the association between paternal age and risk for stillbirth in offspring.
Conclusion: The risk of stillbirth may be slightly increased for older fathers. Low certainty of evidence (GRADE⊕⊕○○). It is uncertain whether there is an association between paternal age and NND. Very low certainty of evidence (GRADE⊕○○○).
Birth defects and chromosomal anomalies
Children with birth defects
Five studies assessed children with birth defects, three of high quality, one of medium and one of low quality (Supplementary Table SI, Table II). In a meta-analysis, four of these studies could be included. A small, but significantly higher risk of birth defects was associated with increasing paternal age (pooled estimate 1.05, 95% CI 1.02–1.07) (Fig. 5). The increase was found already at age 35 years and above.
Table IIStudies on the association of paternal age with birth defects and chromosomal anomalies in offspring.
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Study quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Outcomes (risk estimates)
. | Reference group/ controls
. |
---|
Systematic review |
Herkrath et al. (2012), Brazil | Systematic review and meta-analysis | 80 articles included in SR, 13 articles in meta-analysis, 2 articles about increased paternal age | | Paternal age 20–39 years | | Medium |
Original articles n = 47 |
Archer et al. (2007), USA | Cohort study | | Paternal age: Gastroschisis: 20–24 years: APR 1.47 (1.12–1.94) Trisomy 21: 20–24 years: APR 1.28 (1.08–1.51 >40 years: APR 1.05 (0.88–1.24) Trisomy 13: >40 years: APR 0.40 (0.16–0.96) Cleft palate: 20–24 years: APR 1.18 (1.00–1.38) >40 years: APR 0.91 (0.71–1.16) Pyloric stenosis >40 years:APR 0.84 (0.72–0.98) Anencephaly, spina bifida, encephalocele, ASD, VSD (NS)
| Paternal age 25–29 years | Selected birth defects. Adjusted for maternal age, race/ethnicity, parity Totally 18.6% had missing paternal age
| High |
Berg et al. (2015), Norway | Cohort study | 2890 cleft lip (with or without cleft palate) from 2 449 218 births | Paternal age: 30–34 years: ARR 0.89 (0.80–0.98) 35–39 years: ARR 0.91 (0.79–1.04) 40–44: ARR 0.97 (0.80–1.17) 45–49: ARR 1.21 (0.92–1.58) >50: ARR 1.18 (0.78–1.79)
| Paternal age 25–29 years Baseline risk 1.15/1000
| Cleft lip with or without cleft palate Adjusted for maternal age Interaction analysis showed that the risk was increased only if the age was increased in both parents
| High |
Bille et al. (2005), Denmark | Cohort study | 1 489 014 births with 1920 non-syndromic (fewer than 3 associated minor anomalies) cleft lip with or without cleft palate + 956 cleft palate only | Paternal age 20–50 years: per 10 years increase in age AOR 1.12 (1.02–1.22) for cleft lip with or without cleft palate and AOR 1.24 (1.10–1.40) for cleft palate only | No reference group | Cleft lip with or without cleft palate Adjustment for maternal age Both maternal and paternal ages were associated with the risk of cleft lip with or without cleft palate. For cleft palate alone, only paternal age was a risk factor
| High |
Bunin et al. (1997), USA | Case control | 89 cases | Paternal age (mean ± SE) 29.9 ± 0.6 Age difference 1.5 years, P = 0.07 versus controls 30–34 years OR 1.8 (P = 0.05) 35–39 years: OR 0.9 (P = 0.82) ≥40 years: OR 2.9 (P = 0.07)
| | Sporadic neurofibromatosis. Two kind of analyses, one with a control group and another with a reference group Adjustment for maternal age or socio-economic status did not change the results
| Low |
Cross and Hook (1987), USA | Cohort study | 35 680 foetuses with prenatal cytogenetic analysis (amniocentesis, age indication) | No statistically significant effect of any paternal age for trisomy 21 | None | | High |
de Michelena et al. (1993), Peru | Case control | 318 children and teen agers with trisomy 21 | Means of paternal age for all ages, and for maternal age groups <21, 21–29. 30–34, 35–39 and >39 years were similar (P ≥ 0.1) | 1196 controls (4 controls/ cases) | | Low |
De Souza et al. (2009), UK | Case control | 471 cases | No statistically significant association between paternal age and trisomy 21, AOR 1.13 (0.85–1.52) per 10 year increase | 456 controls (parents of children with other disabilities) | | Low |
De Souza and Morris (2010), UK | Case control | 374 cases with trisomy 13, 929 with trisomy 18, 295 with Klinefelter and 28 with XYY syndrome | Per 10 year increase in paternal age (adjusted for the association of trisomy 21 with paternal age = AOR 1.11 [1.01–1.23]): Relative (adjusted) to the population Trisomy 13: AOR 1.10 (0.83–1.45) Trisomy 18: AOR 1.15 (0.96–1.38) Klinefelter: AOR 1.36 (1.02–1.79) XYY: AOR 1.99 (0.75–5.26)
| Population and 5627 controls with trisomy 21 | Trisomy 13, trisomy 18, Klinefelter (XXY), XYY syndrome Controls were matched on maternal age (within 6 months)
| Low |
Dzurova and Pikhart (2005), USA and Czech Republic | Cohort study | | | Paternal age <19 years | Trisomy 21 Adjusted for maternal age, education of mother and sex of infants, 2 years categories Paternal age missing in 17% in Czech Republic
| Medium |
Erickson and Cohen (1974), USA | Case control | 44/56 cases analysed | | Mean paternal age ‘population’ 32.4 years | Apert syndrome, no statistics given | Low |
Erickson (1978), USA | Case control | 4000 white infants with trisomy 21 | No independent effect of paternal age (maternal age and birth order constant), rates at paternal age >45 years were constant | ‘Some’ 86 000 normal white infants | Trisomy 21 | Medium |
Erickson (1979), USA | Cohort study | 2 data sources, Atlanta data: 226 cases and National Centre for Health Statistics (NCHS) data: 1858 cases | Atlanta and NCHS data: no independent paternal age effect using cut off for paternal age ≥40, 45 and 50 years | Atlanta data 161 452 white and 71 193 black controls, NHCS 4597 305 controls | Trisomy 21 | Medium |
Erickson and Bjerkedal (1981), Norway | Cohort study | 693 cases | Small age effect in paternal age ≥50 years | 685 000 controls | | Medium |
Finley et al. (1990), USA | Case control | 14 cases of sporadic blepharophimosis, ptosis, epicanthus inversus, telecanthus complex (BPEI), control data from national means from US statistics | Mean maternal and paternal age higher in cases | US national means 1966–1975 | Blepharophimosis, ptosis, epicanthus inversus, telecanthus complex (BPEI), (autosomal dominant disorder) No statistics given
| Low |
Fisch et al. (2003), USA | Case series | 3419/4387 cases | Effect of paternal age only in mothers >35 years (P = 0.0023) and most pronounced in mothers >40 years (P = 0.0004) | None | Trisomy 21 | Low |
Green et al. (2010), USA | Case control | Cases with birth defects (if n ≥ 100), between 102 to 6629 cases | Paternal age 40 years All orofacial clefts: AOR 1.07 (0.94–1.23) Septal defects: AOR 0.98 (0.87–1.10) Spina bifida: AOR 1.03 (0.82–1.28) Omphalocele: AOR 0.92 (0.64–1.33) Gastroschisis: AOR 0.80 (0.54–1.21)
| Control group of 5839 normal live born infants. Paternal age 30 years. Maternal age 28 years | Selected birth defects Adjusted for paternal race and ethnicity, paternal education, maternal alcohol, maternal smoking, parity, earlier miscarriage, plurality, paternal drug used during pregnancy, use of ART, maternal BMI, folic acid use
| Medium |
Grewal et al. (2012), USA | Case control | 46 114 cases with birth defects | Paternal age: Nervous system anomalies: 38 years: AOR 1.05 (1.00–1.11) 42 years: AOR 1.10 (1.02–1.18) Limb anomalies: 38 years: AOR 1.06 (1.02–1.11) 42 years: AOR 1.11 (1.05–1.18) Integument anomalies: 38 years: AOR 1.05 (1.00–1.09) 42 years: AOR 1.10 (1.03–1.16) For fathers 29 years versus <29 years: Amniotic band syndrome: AOR 0.87 (0.78–0.97) Pyloric stenosis: AOR 0.93 (0.90–0.96) Anomalies of the great veins: AOR 0.93 (0.87–1.00)
| | | Medium |
Harville et al. (2007), Norway | Cohort study | 1431 cases | Paternal age: Cleft palate alone: 30–34 years: AOR 1.00 (0.76–1.31) 35–39 years: AOR 0.94 (0.68–1.30) ≥40 years: AOR 1.10 80.76–1.60)
| Paternal age 20–24 years 1.8 million controls
| | High |
Hook et al. (1981), USA | Cohort study | 551 cases 1952–1963 and 492 cases 1964–1976 | For 1952–1963 there was no significant paternal age effect (36.87 versus 36.82 years) For 1964–1976, paternal age was about half a year greater in cases than in controls (34.55 versus 34.09 years, P < 0.05)
| 418 017 births 1952–1963 418 848 births 1964–1976
| | Medium |
Hook and Cross (1982), USA | Case control | 98 cases of prenatally detected trisomy 21 | Mean difference in paternal age 0.27 (−1.59 to +1.06) | 10 239 foetuses with normal karyotype | | Medium |
Hook and Regal (1984), USA | Case control | 2354 cases with trisomy 21, 116 cases with trisomy 13 (including cases prenatally diagnosed) | No effect of paternal age | Controls were from all live births the same year in New York State | | Low |
Kazaura and Lie (2002), Norway | Cohort study | 1 738 852 infants 1788 trisomy 21
| | None | | High |
Kazaura et al. (2004a), Norway | Cohort study | 291 cases with gastroschisis | Higher risk at young paternal age AOR 1.6 (1.0–2.4) per 10 year decrease in paternal age after adjustment for maternal age, but was not significant after adjustment for paternal year of birth, AOR per year of father’s age: 1.04 (0.99–1.08)
| >1.7 million controls | | High |
Kazaura et al. (2004b), Norway | Cohort study | 1 869 388 births, 42 813 infants with birth defects | Paternal age 45–49 years: CNS defects (not neural tube defects, anencephaly, spina bifida or hydrocephaly) AOR 2.5 (1.2–5.5) Paternal age 20–24 years: Anencephaly AOR 1.4 (1.1–1.8) Neural tube defects. AOR 1.3 (1.1–1.5) Cleft lip: AOR between 0.9–1.2 (NS) Any birth defects: AOR 1.0–1.1 (borderline significant)
| Paternal age 25–29 years | Any and selected birth defects Adjusted for maternal age, parity, maternity institution and year of birth
| High |
Lian et al. (1986), USA | Cohort study | 7490 infants with a major or serious birth defect | Paternal age ≥35 years versus <35 years: ASD: AOR 1.95 (significant) Paternal age ≥40 years versus <40 years: Any birth defect: AOR 1.20 (significant) VSD: AOR 1.69 (significant) Chondrodystrophy: AOR 13.32 (significant) Situs inversus: AOR 19.27 (significant) Paternal age ≥45 versus <45 years Cleft palate/lip: AOR 2.86 (significant) Trisomy 21: NS any age
| 333 624 live born control infants without defects | | Medium |
Lorda-Sanchez et al. (1998), Spain | Case control | 14 cases | Associated with increase in: Paternal age (34.5 ± 6.0 versus 29.6 ± 6.0), OR 1.11 (1.02–1.21) but NS after adjustment for maternal age and no of pregnancies
| 162 controls | Klippel–Trenaunay–Weber syndrome | Low |
Materna-Kiryluk et al. (2009), Polen | Cohort study | 8683 infants 0–2 years with birth defects | AOR (per five years increase in paternal age) Heart defects: AOR 1.05 (1.00–1.09) Cleft lip with or without cleft palate: AOR 1.11 (1.02–1.20) Hypospadia: AOR 1.11 (1.03–1.19) Gastroschisis: AOR 0.69 (0.54–0.90)
| 902 452 population | | High |
McIntosh et al. (1995), USA | Case control | 9431 cases with 22 different birth defects (Trisomy 21, n = 997, cleft palate, n = 1489)
| Neural tube defects Paternal age 40–44, >50 years AORs 1.6 and 2.3 (borderline significant) Reduction of upper limbs 35–39, 40–44 years AORs: 2.1 and 2.4 (significant) Trisomy 21: 40–44, 45–49, ≥50 years AORs 1.5 to 2.0 (significant) Cleft palate: AORs 0.8–1.5 (NS)
| 18 862 controls Paternal age 25–29 years
| | Medium |
Olshan et al. (1994), USA | Case control | 4110 cases with CHD | General increase by paternal age with trend analysis, NS per age group | 8220 controls Paternal age 25–29 years
| | Low |
Orioli et al. (1995), Italy | Case control | 78 cases with achondroplasia (AC) 64 cases with thanatophoric dysplasia (TD) 106 cases with osteogenesis imperfecta (OI)
| | 2 controls per cases Paternal age <30 years Maternal age >30 years
| Achondroplasia (AC), thanatophoric dysplasia (TD), osteogenesis imperfecta (OI), Stratified for maternal age > and <30 years
| Low |
Polednak (1976), USA | Cohort study | 897 orofacial clefts | | 776 642 population Maternal age 25–29 years
| Any and selected birth defects. Stratified for maternal age | Low |
Poletta et al. (2007), South America | Case control | 5128 cleft lip/palate, 1745 cleft palate | Among 3/11 strata (representing 50% of the cases) significant higher risk with paternal age, ORs between 1.42–3.56 | 3712 controls | Orofacial clefts, probably not adjusted for maternal age | Medium/low |
Riccardi et al. (1984), USA | Case series | 187 cases | Paternal age >35 years: 2-fold increase
| | | Low |
Roecker and Huether (1983), USA | Cohort study | 1244 cases | No paternal age effect | 1 672 210 controls | | Low |
Roth et al. (1983a), France | Case control | 118 cases | | 6656 prenatal diagnoses (amniocentesis) | | Low |
Roth et al. (1983b), France | | | | 2 controls per cases in study 2 | | Low |
Stene et al. (1977), Denmark | Case control | 224 cases | Increased risk of trisomy 21 with paternal age >55 years | 5619 controls | | Low |
Stene et al. (1981), Denmark | Case control | 117 cases | Increased risk of trisomy 21 by paternal age >41 years | 5014 prenatal diagnoses | | Low |
Su et al. (2015), China | Cohort study (Denmark) | 15 216 cases with CHDs | | 1 893 899 population Paternal age 25–29 years | CHDs Controlled for maternal age, family history of CHD, maternal infection, gender, parity, parental age difference
| High |
Takano et al. (1992), Japan | Cohort study | 26 cases | No significant effect of paternal age (P = 0.08) | Population controls | Neurofibromatosis | Low |
Tay et al. (1982), Singapore | Case control | 100 cases | No effect of paternal age | 100 controls | Congenital heart disease | Low |
Tellier et al. (1996), France | Cohort study | 41 cases with CHARGE | | Control population not described | CHARGE malformations (coloboma, heart malformation, choanal atresia, retarded growth, genital hypoplasia, ear anomalies and deafness etc) No difference in maternal age
| Low |
Urhoj et al. (2015), Denmark | Cohort study | 10 817 cases with musculoskeletal congenital abnormalities | | 1 605 885 population | Musculoskeletal congenital abnormalities Adjusted for maternal age, year of birth, ethnicity and education
| High |
Vashist et al. (2011), India | Case series | 200 cases with trisomy 21 | Association with paternal age (correlation coeff (r) = 0.04, maternal age constant) | Mean paternal age 31.5 years | Trisomy 21 | Low |
Wolf (1963), USA | Case control | 411 cases with cleft lip and palate | A significant paternal age effect (P < 0.05) | 411 controls | | Low |
Yang et al. (2007), Canada | Cohort study | 77 514 cases with birth defects (Trisomy, n = 13 078, cleft palate, n = 6049)
| Paternal age 35–39, 40–44, 45–49, ≥50 years Any birth defects: AORs: 1.04–1.15 (significant), test for trend P = 0.015 Trisomy 21: AORs 1.19–1.45 (significant), test for trend P < 0.01 Cleft palate: AOR 0.89–1.23 (NS for any age group)
| 5 213 248 population Paternal age 25–29 years
| Any and selected birth defects Advanced paternal age was associated with: Any birth defects, heart defects, tracheo-oesophageal fistula, oesophageal atresia, musculoskeletal/ integumental anomalies, trisomy 21 and other chromosomal anomalies Paternal age <25 years were associated with: Spina bifida/ meningocele, microcephalus, omphalocele/gastroschisis Adjusted for maternal age, race, education, marital status, parity, prenatal care, smoking, alcohol consumption in woman
| High |
Zhan et al. (1991), China | Case control | 497 cases with CHDs | Paternal age <25 years AOR:2.63 (2.12–3.27)
| 6222 controls Paternal age ≥25 years
| | Low |
Zhu et al. (2005b), USA and Denmark | Cohort study | | No overall effect for any birth defect Paternal age >50 years: Trisomy 21 AHR: 4.50 (1.0–20.39) Paternal age 35–39 years: Cleft palate: AHR 1.48 (1.02–2.15) Multiple syndromes, extremities, increased by age, test for trend P < 0.001–0.05
| 71 937 population Paternal age 20–29 years
| Any and selected birth defectsAdjusted for maternal age, parity, maternal and paternal income and education, sex of child and year of birth | High |
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Study quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Outcomes (risk estimates)
. | Reference group/ controls
. |
---|
Systematic review |
Herkrath et al. (2012), Brazil | Systematic review and meta-analysis | 80 articles included in SR, 13 articles in meta-analysis, 2 articles about increased paternal age | | Paternal age 20–39 years | | Medium |
Original articles n = 47 |
Archer et al. (2007), USA | Cohort study | | Paternal age: Gastroschisis: 20–24 years: APR 1.47 (1.12–1.94) Trisomy 21: 20–24 years: APR 1.28 (1.08–1.51 >40 years: APR 1.05 (0.88–1.24) Trisomy 13: >40 years: APR 0.40 (0.16–0.96) Cleft palate: 20–24 years: APR 1.18 (1.00–1.38) >40 years: APR 0.91 (0.71–1.16) Pyloric stenosis >40 years:APR 0.84 (0.72–0.98) Anencephaly, spina bifida, encephalocele, ASD, VSD (NS)
| Paternal age 25–29 years | Selected birth defects. Adjusted for maternal age, race/ethnicity, parity Totally 18.6% had missing paternal age
| High |
Berg et al. (2015), Norway | Cohort study | 2890 cleft lip (with or without cleft palate) from 2 449 218 births | Paternal age: 30–34 years: ARR 0.89 (0.80–0.98) 35–39 years: ARR 0.91 (0.79–1.04) 40–44: ARR 0.97 (0.80–1.17) 45–49: ARR 1.21 (0.92–1.58) >50: ARR 1.18 (0.78–1.79)
| Paternal age 25–29 years Baseline risk 1.15/1000
| Cleft lip with or without cleft palate Adjusted for maternal age Interaction analysis showed that the risk was increased only if the age was increased in both parents
| High |
Bille et al. (2005), Denmark | Cohort study | 1 489 014 births with 1920 non-syndromic (fewer than 3 associated minor anomalies) cleft lip with or without cleft palate + 956 cleft palate only | Paternal age 20–50 years: per 10 years increase in age AOR 1.12 (1.02–1.22) for cleft lip with or without cleft palate and AOR 1.24 (1.10–1.40) for cleft palate only | No reference group | Cleft lip with or without cleft palate Adjustment for maternal age Both maternal and paternal ages were associated with the risk of cleft lip with or without cleft palate. For cleft palate alone, only paternal age was a risk factor
| High |
Bunin et al. (1997), USA | Case control | 89 cases | Paternal age (mean ± SE) 29.9 ± 0.6 Age difference 1.5 years, P = 0.07 versus controls 30–34 years OR 1.8 (P = 0.05) 35–39 years: OR 0.9 (P = 0.82) ≥40 years: OR 2.9 (P = 0.07)
| | Sporadic neurofibromatosis. Two kind of analyses, one with a control group and another with a reference group Adjustment for maternal age or socio-economic status did not change the results
| Low |
Cross and Hook (1987), USA | Cohort study | 35 680 foetuses with prenatal cytogenetic analysis (amniocentesis, age indication) | No statistically significant effect of any paternal age for trisomy 21 | None | | High |
de Michelena et al. (1993), Peru | Case control | 318 children and teen agers with trisomy 21 | Means of paternal age for all ages, and for maternal age groups <21, 21–29. 30–34, 35–39 and >39 years were similar (P ≥ 0.1) | 1196 controls (4 controls/ cases) | | Low |
De Souza et al. (2009), UK | Case control | 471 cases | No statistically significant association between paternal age and trisomy 21, AOR 1.13 (0.85–1.52) per 10 year increase | 456 controls (parents of children with other disabilities) | | Low |
De Souza and Morris (2010), UK | Case control | 374 cases with trisomy 13, 929 with trisomy 18, 295 with Klinefelter and 28 with XYY syndrome | Per 10 year increase in paternal age (adjusted for the association of trisomy 21 with paternal age = AOR 1.11 [1.01–1.23]): Relative (adjusted) to the population Trisomy 13: AOR 1.10 (0.83–1.45) Trisomy 18: AOR 1.15 (0.96–1.38) Klinefelter: AOR 1.36 (1.02–1.79) XYY: AOR 1.99 (0.75–5.26)
| Population and 5627 controls with trisomy 21 | Trisomy 13, trisomy 18, Klinefelter (XXY), XYY syndrome Controls were matched on maternal age (within 6 months)
| Low |
Dzurova and Pikhart (2005), USA and Czech Republic | Cohort study | | | Paternal age <19 years | Trisomy 21 Adjusted for maternal age, education of mother and sex of infants, 2 years categories Paternal age missing in 17% in Czech Republic
| Medium |
Erickson and Cohen (1974), USA | Case control | 44/56 cases analysed | | Mean paternal age ‘population’ 32.4 years | Apert syndrome, no statistics given | Low |
Erickson (1978), USA | Case control | 4000 white infants with trisomy 21 | No independent effect of paternal age (maternal age and birth order constant), rates at paternal age >45 years were constant | ‘Some’ 86 000 normal white infants | Trisomy 21 | Medium |
Erickson (1979), USA | Cohort study | 2 data sources, Atlanta data: 226 cases and National Centre for Health Statistics (NCHS) data: 1858 cases | Atlanta and NCHS data: no independent paternal age effect using cut off for paternal age ≥40, 45 and 50 years | Atlanta data 161 452 white and 71 193 black controls, NHCS 4597 305 controls | Trisomy 21 | Medium |
Erickson and Bjerkedal (1981), Norway | Cohort study | 693 cases | Small age effect in paternal age ≥50 years | 685 000 controls | | Medium |
Finley et al. (1990), USA | Case control | 14 cases of sporadic blepharophimosis, ptosis, epicanthus inversus, telecanthus complex (BPEI), control data from national means from US statistics | Mean maternal and paternal age higher in cases | US national means 1966–1975 | Blepharophimosis, ptosis, epicanthus inversus, telecanthus complex (BPEI), (autosomal dominant disorder) No statistics given
| Low |
Fisch et al. (2003), USA | Case series | 3419/4387 cases | Effect of paternal age only in mothers >35 years (P = 0.0023) and most pronounced in mothers >40 years (P = 0.0004) | None | Trisomy 21 | Low |
Green et al. (2010), USA | Case control | Cases with birth defects (if n ≥ 100), between 102 to 6629 cases | Paternal age 40 years All orofacial clefts: AOR 1.07 (0.94–1.23) Septal defects: AOR 0.98 (0.87–1.10) Spina bifida: AOR 1.03 (0.82–1.28) Omphalocele: AOR 0.92 (0.64–1.33) Gastroschisis: AOR 0.80 (0.54–1.21)
| Control group of 5839 normal live born infants. Paternal age 30 years. Maternal age 28 years | Selected birth defects Adjusted for paternal race and ethnicity, paternal education, maternal alcohol, maternal smoking, parity, earlier miscarriage, plurality, paternal drug used during pregnancy, use of ART, maternal BMI, folic acid use
| Medium |
Grewal et al. (2012), USA | Case control | 46 114 cases with birth defects | Paternal age: Nervous system anomalies: 38 years: AOR 1.05 (1.00–1.11) 42 years: AOR 1.10 (1.02–1.18) Limb anomalies: 38 years: AOR 1.06 (1.02–1.11) 42 years: AOR 1.11 (1.05–1.18) Integument anomalies: 38 years: AOR 1.05 (1.00–1.09) 42 years: AOR 1.10 (1.03–1.16) For fathers 29 years versus <29 years: Amniotic band syndrome: AOR 0.87 (0.78–0.97) Pyloric stenosis: AOR 0.93 (0.90–0.96) Anomalies of the great veins: AOR 0.93 (0.87–1.00)
| | | Medium |
Harville et al. (2007), Norway | Cohort study | 1431 cases | Paternal age: Cleft palate alone: 30–34 years: AOR 1.00 (0.76–1.31) 35–39 years: AOR 0.94 (0.68–1.30) ≥40 years: AOR 1.10 80.76–1.60)
| Paternal age 20–24 years 1.8 million controls
| | High |
Hook et al. (1981), USA | Cohort study | 551 cases 1952–1963 and 492 cases 1964–1976 | For 1952–1963 there was no significant paternal age effect (36.87 versus 36.82 years) For 1964–1976, paternal age was about half a year greater in cases than in controls (34.55 versus 34.09 years, P < 0.05)
| 418 017 births 1952–1963 418 848 births 1964–1976
| | Medium |
Hook and Cross (1982), USA | Case control | 98 cases of prenatally detected trisomy 21 | Mean difference in paternal age 0.27 (−1.59 to +1.06) | 10 239 foetuses with normal karyotype | | Medium |
Hook and Regal (1984), USA | Case control | 2354 cases with trisomy 21, 116 cases with trisomy 13 (including cases prenatally diagnosed) | No effect of paternal age | Controls were from all live births the same year in New York State | | Low |
Kazaura and Lie (2002), Norway | Cohort study | 1 738 852 infants 1788 trisomy 21
| | None | | High |
Kazaura et al. (2004a), Norway | Cohort study | 291 cases with gastroschisis | Higher risk at young paternal age AOR 1.6 (1.0–2.4) per 10 year decrease in paternal age after adjustment for maternal age, but was not significant after adjustment for paternal year of birth, AOR per year of father’s age: 1.04 (0.99–1.08)
| >1.7 million controls | | High |
Kazaura et al. (2004b), Norway | Cohort study | 1 869 388 births, 42 813 infants with birth defects | Paternal age 45–49 years: CNS defects (not neural tube defects, anencephaly, spina bifida or hydrocephaly) AOR 2.5 (1.2–5.5) Paternal age 20–24 years: Anencephaly AOR 1.4 (1.1–1.8) Neural tube defects. AOR 1.3 (1.1–1.5) Cleft lip: AOR between 0.9–1.2 (NS) Any birth defects: AOR 1.0–1.1 (borderline significant)
| Paternal age 25–29 years | Any and selected birth defects Adjusted for maternal age, parity, maternity institution and year of birth
| High |
Lian et al. (1986), USA | Cohort study | 7490 infants with a major or serious birth defect | Paternal age ≥35 years versus <35 years: ASD: AOR 1.95 (significant) Paternal age ≥40 years versus <40 years: Any birth defect: AOR 1.20 (significant) VSD: AOR 1.69 (significant) Chondrodystrophy: AOR 13.32 (significant) Situs inversus: AOR 19.27 (significant) Paternal age ≥45 versus <45 years Cleft palate/lip: AOR 2.86 (significant) Trisomy 21: NS any age
| 333 624 live born control infants without defects | | Medium |
Lorda-Sanchez et al. (1998), Spain | Case control | 14 cases | Associated with increase in: Paternal age (34.5 ± 6.0 versus 29.6 ± 6.0), OR 1.11 (1.02–1.21) but NS after adjustment for maternal age and no of pregnancies
| 162 controls | Klippel–Trenaunay–Weber syndrome | Low |
Materna-Kiryluk et al. (2009), Polen | Cohort study | 8683 infants 0–2 years with birth defects | AOR (per five years increase in paternal age) Heart defects: AOR 1.05 (1.00–1.09) Cleft lip with or without cleft palate: AOR 1.11 (1.02–1.20) Hypospadia: AOR 1.11 (1.03–1.19) Gastroschisis: AOR 0.69 (0.54–0.90)
| 902 452 population | | High |
McIntosh et al. (1995), USA | Case control | 9431 cases with 22 different birth defects (Trisomy 21, n = 997, cleft palate, n = 1489)
| Neural tube defects Paternal age 40–44, >50 years AORs 1.6 and 2.3 (borderline significant) Reduction of upper limbs 35–39, 40–44 years AORs: 2.1 and 2.4 (significant) Trisomy 21: 40–44, 45–49, ≥50 years AORs 1.5 to 2.0 (significant) Cleft palate: AORs 0.8–1.5 (NS)
| 18 862 controls Paternal age 25–29 years
| | Medium |
Olshan et al. (1994), USA | Case control | 4110 cases with CHD | General increase by paternal age with trend analysis, NS per age group | 8220 controls Paternal age 25–29 years
| | Low |
Orioli et al. (1995), Italy | Case control | 78 cases with achondroplasia (AC) 64 cases with thanatophoric dysplasia (TD) 106 cases with osteogenesis imperfecta (OI)
| | 2 controls per cases Paternal age <30 years Maternal age >30 years
| Achondroplasia (AC), thanatophoric dysplasia (TD), osteogenesis imperfecta (OI), Stratified for maternal age > and <30 years
| Low |
Polednak (1976), USA | Cohort study | 897 orofacial clefts | | 776 642 population Maternal age 25–29 years
| Any and selected birth defects. Stratified for maternal age | Low |
Poletta et al. (2007), South America | Case control | 5128 cleft lip/palate, 1745 cleft palate | Among 3/11 strata (representing 50% of the cases) significant higher risk with paternal age, ORs between 1.42–3.56 | 3712 controls | Orofacial clefts, probably not adjusted for maternal age | Medium/low |
Riccardi et al. (1984), USA | Case series | 187 cases | Paternal age >35 years: 2-fold increase
| | | Low |
Roecker and Huether (1983), USA | Cohort study | 1244 cases | No paternal age effect | 1 672 210 controls | | Low |
Roth et al. (1983a), France | Case control | 118 cases | | 6656 prenatal diagnoses (amniocentesis) | | Low |
Roth et al. (1983b), France | | | | 2 controls per cases in study 2 | | Low |
Stene et al. (1977), Denmark | Case control | 224 cases | Increased risk of trisomy 21 with paternal age >55 years | 5619 controls | | Low |
Stene et al. (1981), Denmark | Case control | 117 cases | Increased risk of trisomy 21 by paternal age >41 years | 5014 prenatal diagnoses | | Low |
Su et al. (2015), China | Cohort study (Denmark) | 15 216 cases with CHDs | | 1 893 899 population Paternal age 25–29 years | CHDs Controlled for maternal age, family history of CHD, maternal infection, gender, parity, parental age difference
| High |
Takano et al. (1992), Japan | Cohort study | 26 cases | No significant effect of paternal age (P = 0.08) | Population controls | Neurofibromatosis | Low |
Tay et al. (1982), Singapore | Case control | 100 cases | No effect of paternal age | 100 controls | Congenital heart disease | Low |
Tellier et al. (1996), France | Cohort study | 41 cases with CHARGE | | Control population not described | CHARGE malformations (coloboma, heart malformation, choanal atresia, retarded growth, genital hypoplasia, ear anomalies and deafness etc) No difference in maternal age
| Low |
Urhoj et al. (2015), Denmark | Cohort study | 10 817 cases with musculoskeletal congenital abnormalities | | 1 605 885 population | Musculoskeletal congenital abnormalities Adjusted for maternal age, year of birth, ethnicity and education
| High |
Vashist et al. (2011), India | Case series | 200 cases with trisomy 21 | Association with paternal age (correlation coeff (r) = 0.04, maternal age constant) | Mean paternal age 31.5 years | Trisomy 21 | Low |
Wolf (1963), USA | Case control | 411 cases with cleft lip and palate | A significant paternal age effect (P < 0.05) | 411 controls | | Low |
Yang et al. (2007), Canada | Cohort study | 77 514 cases with birth defects (Trisomy, n = 13 078, cleft palate, n = 6049)
| Paternal age 35–39, 40–44, 45–49, ≥50 years Any birth defects: AORs: 1.04–1.15 (significant), test for trend P = 0.015 Trisomy 21: AORs 1.19–1.45 (significant), test for trend P < 0.01 Cleft palate: AOR 0.89–1.23 (NS for any age group)
| 5 213 248 population Paternal age 25–29 years
| Any and selected birth defects Advanced paternal age was associated with: Any birth defects, heart defects, tracheo-oesophageal fistula, oesophageal atresia, musculoskeletal/ integumental anomalies, trisomy 21 and other chromosomal anomalies Paternal age <25 years were associated with: Spina bifida/ meningocele, microcephalus, omphalocele/gastroschisis Adjusted for maternal age, race, education, marital status, parity, prenatal care, smoking, alcohol consumption in woman
| High |
Zhan et al. (1991), China | Case control | 497 cases with CHDs | Paternal age <25 years AOR:2.63 (2.12–3.27)
| 6222 controls Paternal age ≥25 years
| | Low |
Zhu et al. (2005b), USA and Denmark | Cohort study | | No overall effect for any birth defect Paternal age >50 years: Trisomy 21 AHR: 4.50 (1.0–20.39) Paternal age 35–39 years: Cleft palate: AHR 1.48 (1.02–2.15) Multiple syndromes, extremities, increased by age, test for trend P < 0.001–0.05
| 71 937 population Paternal age 20–29 years
| Any and selected birth defectsAdjusted for maternal age, parity, maternal and paternal income and education, sex of child and year of birth | High |
Table IIStudies on the association of paternal age with birth defects and chromosomal anomalies in offspring.
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Study quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Outcomes (risk estimates)
. | Reference group/ controls
. |
---|
Systematic review |
Herkrath et al. (2012), Brazil | Systematic review and meta-analysis | 80 articles included in SR, 13 articles in meta-analysis, 2 articles about increased paternal age | | Paternal age 20–39 years | | Medium |
Original articles n = 47 |
Archer et al. (2007), USA | Cohort study | | Paternal age: Gastroschisis: 20–24 years: APR 1.47 (1.12–1.94) Trisomy 21: 20–24 years: APR 1.28 (1.08–1.51 >40 years: APR 1.05 (0.88–1.24) Trisomy 13: >40 years: APR 0.40 (0.16–0.96) Cleft palate: 20–24 years: APR 1.18 (1.00–1.38) >40 years: APR 0.91 (0.71–1.16) Pyloric stenosis >40 years:APR 0.84 (0.72–0.98) Anencephaly, spina bifida, encephalocele, ASD, VSD (NS)
| Paternal age 25–29 years | Selected birth defects. Adjusted for maternal age, race/ethnicity, parity Totally 18.6% had missing paternal age
| High |
Berg et al. (2015), Norway | Cohort study | 2890 cleft lip (with or without cleft palate) from 2 449 218 births | Paternal age: 30–34 years: ARR 0.89 (0.80–0.98) 35–39 years: ARR 0.91 (0.79–1.04) 40–44: ARR 0.97 (0.80–1.17) 45–49: ARR 1.21 (0.92–1.58) >50: ARR 1.18 (0.78–1.79)
| Paternal age 25–29 years Baseline risk 1.15/1000
| Cleft lip with or without cleft palate Adjusted for maternal age Interaction analysis showed that the risk was increased only if the age was increased in both parents
| High |
Bille et al. (2005), Denmark | Cohort study | 1 489 014 births with 1920 non-syndromic (fewer than 3 associated minor anomalies) cleft lip with or without cleft palate + 956 cleft palate only | Paternal age 20–50 years: per 10 years increase in age AOR 1.12 (1.02–1.22) for cleft lip with or without cleft palate and AOR 1.24 (1.10–1.40) for cleft palate only | No reference group | Cleft lip with or without cleft palate Adjustment for maternal age Both maternal and paternal ages were associated with the risk of cleft lip with or without cleft palate. For cleft palate alone, only paternal age was a risk factor
| High |
Bunin et al. (1997), USA | Case control | 89 cases | Paternal age (mean ± SE) 29.9 ± 0.6 Age difference 1.5 years, P = 0.07 versus controls 30–34 years OR 1.8 (P = 0.05) 35–39 years: OR 0.9 (P = 0.82) ≥40 years: OR 2.9 (P = 0.07)
| | Sporadic neurofibromatosis. Two kind of analyses, one with a control group and another with a reference group Adjustment for maternal age or socio-economic status did not change the results
| Low |
Cross and Hook (1987), USA | Cohort study | 35 680 foetuses with prenatal cytogenetic analysis (amniocentesis, age indication) | No statistically significant effect of any paternal age for trisomy 21 | None | | High |
de Michelena et al. (1993), Peru | Case control | 318 children and teen agers with trisomy 21 | Means of paternal age for all ages, and for maternal age groups <21, 21–29. 30–34, 35–39 and >39 years were similar (P ≥ 0.1) | 1196 controls (4 controls/ cases) | | Low |
De Souza et al. (2009), UK | Case control | 471 cases | No statistically significant association between paternal age and trisomy 21, AOR 1.13 (0.85–1.52) per 10 year increase | 456 controls (parents of children with other disabilities) | | Low |
De Souza and Morris (2010), UK | Case control | 374 cases with trisomy 13, 929 with trisomy 18, 295 with Klinefelter and 28 with XYY syndrome | Per 10 year increase in paternal age (adjusted for the association of trisomy 21 with paternal age = AOR 1.11 [1.01–1.23]): Relative (adjusted) to the population Trisomy 13: AOR 1.10 (0.83–1.45) Trisomy 18: AOR 1.15 (0.96–1.38) Klinefelter: AOR 1.36 (1.02–1.79) XYY: AOR 1.99 (0.75–5.26)
| Population and 5627 controls with trisomy 21 | Trisomy 13, trisomy 18, Klinefelter (XXY), XYY syndrome Controls were matched on maternal age (within 6 months)
| Low |
Dzurova and Pikhart (2005), USA and Czech Republic | Cohort study | | | Paternal age <19 years | Trisomy 21 Adjusted for maternal age, education of mother and sex of infants, 2 years categories Paternal age missing in 17% in Czech Republic
| Medium |
Erickson and Cohen (1974), USA | Case control | 44/56 cases analysed | | Mean paternal age ‘population’ 32.4 years | Apert syndrome, no statistics given | Low |
Erickson (1978), USA | Case control | 4000 white infants with trisomy 21 | No independent effect of paternal age (maternal age and birth order constant), rates at paternal age >45 years were constant | ‘Some’ 86 000 normal white infants | Trisomy 21 | Medium |
Erickson (1979), USA | Cohort study | 2 data sources, Atlanta data: 226 cases and National Centre for Health Statistics (NCHS) data: 1858 cases | Atlanta and NCHS data: no independent paternal age effect using cut off for paternal age ≥40, 45 and 50 years | Atlanta data 161 452 white and 71 193 black controls, NHCS 4597 305 controls | Trisomy 21 | Medium |
Erickson and Bjerkedal (1981), Norway | Cohort study | 693 cases | Small age effect in paternal age ≥50 years | 685 000 controls | | Medium |
Finley et al. (1990), USA | Case control | 14 cases of sporadic blepharophimosis, ptosis, epicanthus inversus, telecanthus complex (BPEI), control data from national means from US statistics | Mean maternal and paternal age higher in cases | US national means 1966–1975 | Blepharophimosis, ptosis, epicanthus inversus, telecanthus complex (BPEI), (autosomal dominant disorder) No statistics given
| Low |
Fisch et al. (2003), USA | Case series | 3419/4387 cases | Effect of paternal age only in mothers >35 years (P = 0.0023) and most pronounced in mothers >40 years (P = 0.0004) | None | Trisomy 21 | Low |
Green et al. (2010), USA | Case control | Cases with birth defects (if n ≥ 100), between 102 to 6629 cases | Paternal age 40 years All orofacial clefts: AOR 1.07 (0.94–1.23) Septal defects: AOR 0.98 (0.87–1.10) Spina bifida: AOR 1.03 (0.82–1.28) Omphalocele: AOR 0.92 (0.64–1.33) Gastroschisis: AOR 0.80 (0.54–1.21)
| Control group of 5839 normal live born infants. Paternal age 30 years. Maternal age 28 years | Selected birth defects Adjusted for paternal race and ethnicity, paternal education, maternal alcohol, maternal smoking, parity, earlier miscarriage, plurality, paternal drug used during pregnancy, use of ART, maternal BMI, folic acid use
| Medium |
Grewal et al. (2012), USA | Case control | 46 114 cases with birth defects | Paternal age: Nervous system anomalies: 38 years: AOR 1.05 (1.00–1.11) 42 years: AOR 1.10 (1.02–1.18) Limb anomalies: 38 years: AOR 1.06 (1.02–1.11) 42 years: AOR 1.11 (1.05–1.18) Integument anomalies: 38 years: AOR 1.05 (1.00–1.09) 42 years: AOR 1.10 (1.03–1.16) For fathers 29 years versus <29 years: Amniotic band syndrome: AOR 0.87 (0.78–0.97) Pyloric stenosis: AOR 0.93 (0.90–0.96) Anomalies of the great veins: AOR 0.93 (0.87–1.00)
| | | Medium |
Harville et al. (2007), Norway | Cohort study | 1431 cases | Paternal age: Cleft palate alone: 30–34 years: AOR 1.00 (0.76–1.31) 35–39 years: AOR 0.94 (0.68–1.30) ≥40 years: AOR 1.10 80.76–1.60)
| Paternal age 20–24 years 1.8 million controls
| | High |
Hook et al. (1981), USA | Cohort study | 551 cases 1952–1963 and 492 cases 1964–1976 | For 1952–1963 there was no significant paternal age effect (36.87 versus 36.82 years) For 1964–1976, paternal age was about half a year greater in cases than in controls (34.55 versus 34.09 years, P < 0.05)
| 418 017 births 1952–1963 418 848 births 1964–1976
| | Medium |
Hook and Cross (1982), USA | Case control | 98 cases of prenatally detected trisomy 21 | Mean difference in paternal age 0.27 (−1.59 to +1.06) | 10 239 foetuses with normal karyotype | | Medium |
Hook and Regal (1984), USA | Case control | 2354 cases with trisomy 21, 116 cases with trisomy 13 (including cases prenatally diagnosed) | No effect of paternal age | Controls were from all live births the same year in New York State | | Low |
Kazaura and Lie (2002), Norway | Cohort study | 1 738 852 infants 1788 trisomy 21
| | None | | High |
Kazaura et al. (2004a), Norway | Cohort study | 291 cases with gastroschisis | Higher risk at young paternal age AOR 1.6 (1.0–2.4) per 10 year decrease in paternal age after adjustment for maternal age, but was not significant after adjustment for paternal year of birth, AOR per year of father’s age: 1.04 (0.99–1.08)
| >1.7 million controls | | High |
Kazaura et al. (2004b), Norway | Cohort study | 1 869 388 births, 42 813 infants with birth defects | Paternal age 45–49 years: CNS defects (not neural tube defects, anencephaly, spina bifida or hydrocephaly) AOR 2.5 (1.2–5.5) Paternal age 20–24 years: Anencephaly AOR 1.4 (1.1–1.8) Neural tube defects. AOR 1.3 (1.1–1.5) Cleft lip: AOR between 0.9–1.2 (NS) Any birth defects: AOR 1.0–1.1 (borderline significant)
| Paternal age 25–29 years | Any and selected birth defects Adjusted for maternal age, parity, maternity institution and year of birth
| High |
Lian et al. (1986), USA | Cohort study | 7490 infants with a major or serious birth defect | Paternal age ≥35 years versus <35 years: ASD: AOR 1.95 (significant) Paternal age ≥40 years versus <40 years: Any birth defect: AOR 1.20 (significant) VSD: AOR 1.69 (significant) Chondrodystrophy: AOR 13.32 (significant) Situs inversus: AOR 19.27 (significant) Paternal age ≥45 versus <45 years Cleft palate/lip: AOR 2.86 (significant) Trisomy 21: NS any age
| 333 624 live born control infants without defects | | Medium |
Lorda-Sanchez et al. (1998), Spain | Case control | 14 cases | Associated with increase in: Paternal age (34.5 ± 6.0 versus 29.6 ± 6.0), OR 1.11 (1.02–1.21) but NS after adjustment for maternal age and no of pregnancies
| 162 controls | Klippel–Trenaunay–Weber syndrome | Low |
Materna-Kiryluk et al. (2009), Polen | Cohort study | 8683 infants 0–2 years with birth defects | AOR (per five years increase in paternal age) Heart defects: AOR 1.05 (1.00–1.09) Cleft lip with or without cleft palate: AOR 1.11 (1.02–1.20) Hypospadia: AOR 1.11 (1.03–1.19) Gastroschisis: AOR 0.69 (0.54–0.90)
| 902 452 population | | High |
McIntosh et al. (1995), USA | Case control | 9431 cases with 22 different birth defects (Trisomy 21, n = 997, cleft palate, n = 1489)
| Neural tube defects Paternal age 40–44, >50 years AORs 1.6 and 2.3 (borderline significant) Reduction of upper limbs 35–39, 40–44 years AORs: 2.1 and 2.4 (significant) Trisomy 21: 40–44, 45–49, ≥50 years AORs 1.5 to 2.0 (significant) Cleft palate: AORs 0.8–1.5 (NS)
| 18 862 controls Paternal age 25–29 years
| | Medium |
Olshan et al. (1994), USA | Case control | 4110 cases with CHD | General increase by paternal age with trend analysis, NS per age group | 8220 controls Paternal age 25–29 years
| | Low |
Orioli et al. (1995), Italy | Case control | 78 cases with achondroplasia (AC) 64 cases with thanatophoric dysplasia (TD) 106 cases with osteogenesis imperfecta (OI)
| | 2 controls per cases Paternal age <30 years Maternal age >30 years
| Achondroplasia (AC), thanatophoric dysplasia (TD), osteogenesis imperfecta (OI), Stratified for maternal age > and <30 years
| Low |
Polednak (1976), USA | Cohort study | 897 orofacial clefts | | 776 642 population Maternal age 25–29 years
| Any and selected birth defects. Stratified for maternal age | Low |
Poletta et al. (2007), South America | Case control | 5128 cleft lip/palate, 1745 cleft palate | Among 3/11 strata (representing 50% of the cases) significant higher risk with paternal age, ORs between 1.42–3.56 | 3712 controls | Orofacial clefts, probably not adjusted for maternal age | Medium/low |
Riccardi et al. (1984), USA | Case series | 187 cases | Paternal age >35 years: 2-fold increase
| | | Low |
Roecker and Huether (1983), USA | Cohort study | 1244 cases | No paternal age effect | 1 672 210 controls | | Low |
Roth et al. (1983a), France | Case control | 118 cases | | 6656 prenatal diagnoses (amniocentesis) | | Low |
Roth et al. (1983b), France | | | | 2 controls per cases in study 2 | | Low |
Stene et al. (1977), Denmark | Case control | 224 cases | Increased risk of trisomy 21 with paternal age >55 years | 5619 controls | | Low |
Stene et al. (1981), Denmark | Case control | 117 cases | Increased risk of trisomy 21 by paternal age >41 years | 5014 prenatal diagnoses | | Low |
Su et al. (2015), China | Cohort study (Denmark) | 15 216 cases with CHDs | | 1 893 899 population Paternal age 25–29 years | CHDs Controlled for maternal age, family history of CHD, maternal infection, gender, parity, parental age difference
| High |
Takano et al. (1992), Japan | Cohort study | 26 cases | No significant effect of paternal age (P = 0.08) | Population controls | Neurofibromatosis | Low |
Tay et al. (1982), Singapore | Case control | 100 cases | No effect of paternal age | 100 controls | Congenital heart disease | Low |
Tellier et al. (1996), France | Cohort study | 41 cases with CHARGE | | Control population not described | CHARGE malformations (coloboma, heart malformation, choanal atresia, retarded growth, genital hypoplasia, ear anomalies and deafness etc) No difference in maternal age
| Low |
Urhoj et al. (2015), Denmark | Cohort study | 10 817 cases with musculoskeletal congenital abnormalities | | 1 605 885 population | Musculoskeletal congenital abnormalities Adjusted for maternal age, year of birth, ethnicity and education
| High |
Vashist et al. (2011), India | Case series | 200 cases with trisomy 21 | Association with paternal age (correlation coeff (r) = 0.04, maternal age constant) | Mean paternal age 31.5 years | Trisomy 21 | Low |
Wolf (1963), USA | Case control | 411 cases with cleft lip and palate | A significant paternal age effect (P < 0.05) | 411 controls | | Low |
Yang et al. (2007), Canada | Cohort study | 77 514 cases with birth defects (Trisomy, n = 13 078, cleft palate, n = 6049)
| Paternal age 35–39, 40–44, 45–49, ≥50 years Any birth defects: AORs: 1.04–1.15 (significant), test for trend P = 0.015 Trisomy 21: AORs 1.19–1.45 (significant), test for trend P < 0.01 Cleft palate: AOR 0.89–1.23 (NS for any age group)
| 5 213 248 population Paternal age 25–29 years
| Any and selected birth defects Advanced paternal age was associated with: Any birth defects, heart defects, tracheo-oesophageal fistula, oesophageal atresia, musculoskeletal/ integumental anomalies, trisomy 21 and other chromosomal anomalies Paternal age <25 years were associated with: Spina bifida/ meningocele, microcephalus, omphalocele/gastroschisis Adjusted for maternal age, race, education, marital status, parity, prenatal care, smoking, alcohol consumption in woman
| High |
Zhan et al. (1991), China | Case control | 497 cases with CHDs | Paternal age <25 years AOR:2.63 (2.12–3.27)
| 6222 controls Paternal age ≥25 years
| | Low |
Zhu et al. (2005b), USA and Denmark | Cohort study | | No overall effect for any birth defect Paternal age >50 years: Trisomy 21 AHR: 4.50 (1.0–20.39) Paternal age 35–39 years: Cleft palate: AHR 1.48 (1.02–2.15) Multiple syndromes, extremities, increased by age, test for trend P < 0.001–0.05
| 71 937 population Paternal age 20–29 years
| Any and selected birth defectsAdjusted for maternal age, parity, maternal and paternal income and education, sex of child and year of birth | High |
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Study quality
. |
---|
Comments
. |
---|
Adjustments
. |
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Outcomes (risk estimates)
. | Reference group/ controls
. |
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Systematic review |
Herkrath et al. (2012), Brazil | Systematic review and meta-analysis | 80 articles included in SR, 13 articles in meta-analysis, 2 articles about increased paternal age | | Paternal age 20–39 years | | Medium |
Original articles n = 47 |
Archer et al. (2007), USA | Cohort study | | Paternal age: Gastroschisis: 20–24 years: APR 1.47 (1.12–1.94) Trisomy 21: 20–24 years: APR 1.28 (1.08–1.51 >40 years: APR 1.05 (0.88–1.24) Trisomy 13: >40 years: APR 0.40 (0.16–0.96) Cleft palate: 20–24 years: APR 1.18 (1.00–1.38) >40 years: APR 0.91 (0.71–1.16) Pyloric stenosis >40 years:APR 0.84 (0.72–0.98) Anencephaly, spina bifida, encephalocele, ASD, VSD (NS)
| Paternal age 25–29 years | Selected birth defects. Adjusted for maternal age, race/ethnicity, parity Totally 18.6% had missing paternal age
| High |
Berg et al. (2015), Norway | Cohort study | 2890 cleft lip (with or without cleft palate) from 2 449 218 births | Paternal age: 30–34 years: ARR 0.89 (0.80–0.98) 35–39 years: ARR 0.91 (0.79–1.04) 40–44: ARR 0.97 (0.80–1.17) 45–49: ARR 1.21 (0.92–1.58) >50: ARR 1.18 (0.78–1.79)
| Paternal age 25–29 years Baseline risk 1.15/1000
| Cleft lip with or without cleft palate Adjusted for maternal age Interaction analysis showed that the risk was increased only if the age was increased in both parents
| High |
Bille et al. (2005), Denmark | Cohort study | 1 489 014 births with 1920 non-syndromic (fewer than 3 associated minor anomalies) cleft lip with or without cleft palate + 956 cleft palate only | Paternal age 20–50 years: per 10 years increase in age AOR 1.12 (1.02–1.22) for cleft lip with or without cleft palate and AOR 1.24 (1.10–1.40) for cleft palate only | No reference group | Cleft lip with or without cleft palate Adjustment for maternal age Both maternal and paternal ages were associated with the risk of cleft lip with or without cleft palate. For cleft palate alone, only paternal age was a risk factor
| High |
Bunin et al. (1997), USA | Case control | 89 cases | Paternal age (mean ± SE) 29.9 ± 0.6 Age difference 1.5 years, P = 0.07 versus controls 30–34 years OR 1.8 (P = 0.05) 35–39 years: OR 0.9 (P = 0.82) ≥40 years: OR 2.9 (P = 0.07)
| | Sporadic neurofibromatosis. Two kind of analyses, one with a control group and another with a reference group Adjustment for maternal age or socio-economic status did not change the results
| Low |
Cross and Hook (1987), USA | Cohort study | 35 680 foetuses with prenatal cytogenetic analysis (amniocentesis, age indication) | No statistically significant effect of any paternal age for trisomy 21 | None | | High |
de Michelena et al. (1993), Peru | Case control | 318 children and teen agers with trisomy 21 | Means of paternal age for all ages, and for maternal age groups <21, 21–29. 30–34, 35–39 and >39 years were similar (P ≥ 0.1) | 1196 controls (4 controls/ cases) | | Low |
De Souza et al. (2009), UK | Case control | 471 cases | No statistically significant association between paternal age and trisomy 21, AOR 1.13 (0.85–1.52) per 10 year increase | 456 controls (parents of children with other disabilities) | | Low |
De Souza and Morris (2010), UK | Case control | 374 cases with trisomy 13, 929 with trisomy 18, 295 with Klinefelter and 28 with XYY syndrome | Per 10 year increase in paternal age (adjusted for the association of trisomy 21 with paternal age = AOR 1.11 [1.01–1.23]): Relative (adjusted) to the population Trisomy 13: AOR 1.10 (0.83–1.45) Trisomy 18: AOR 1.15 (0.96–1.38) Klinefelter: AOR 1.36 (1.02–1.79) XYY: AOR 1.99 (0.75–5.26)
| Population and 5627 controls with trisomy 21 | Trisomy 13, trisomy 18, Klinefelter (XXY), XYY syndrome Controls were matched on maternal age (within 6 months)
| Low |
Dzurova and Pikhart (2005), USA and Czech Republic | Cohort study | | | Paternal age <19 years | Trisomy 21 Adjusted for maternal age, education of mother and sex of infants, 2 years categories Paternal age missing in 17% in Czech Republic
| Medium |
Erickson and Cohen (1974), USA | Case control | 44/56 cases analysed | | Mean paternal age ‘population’ 32.4 years | Apert syndrome, no statistics given | Low |
Erickson (1978), USA | Case control | 4000 white infants with trisomy 21 | No independent effect of paternal age (maternal age and birth order constant), rates at paternal age >45 years were constant | ‘Some’ 86 000 normal white infants | Trisomy 21 | Medium |
Erickson (1979), USA | Cohort study | 2 data sources, Atlanta data: 226 cases and National Centre for Health Statistics (NCHS) data: 1858 cases | Atlanta and NCHS data: no independent paternal age effect using cut off for paternal age ≥40, 45 and 50 years | Atlanta data 161 452 white and 71 193 black controls, NHCS 4597 305 controls | Trisomy 21 | Medium |
Erickson and Bjerkedal (1981), Norway | Cohort study | 693 cases | Small age effect in paternal age ≥50 years | 685 000 controls | | Medium |
Finley et al. (1990), USA | Case control | 14 cases of sporadic blepharophimosis, ptosis, epicanthus inversus, telecanthus complex (BPEI), control data from national means from US statistics | Mean maternal and paternal age higher in cases | US national means 1966–1975 | Blepharophimosis, ptosis, epicanthus inversus, telecanthus complex (BPEI), (autosomal dominant disorder) No statistics given
| Low |
Fisch et al. (2003), USA | Case series | 3419/4387 cases | Effect of paternal age only in mothers >35 years (P = 0.0023) and most pronounced in mothers >40 years (P = 0.0004) | None | Trisomy 21 | Low |
Green et al. (2010), USA | Case control | Cases with birth defects (if n ≥ 100), between 102 to 6629 cases | Paternal age 40 years All orofacial clefts: AOR 1.07 (0.94–1.23) Septal defects: AOR 0.98 (0.87–1.10) Spina bifida: AOR 1.03 (0.82–1.28) Omphalocele: AOR 0.92 (0.64–1.33) Gastroschisis: AOR 0.80 (0.54–1.21)
| Control group of 5839 normal live born infants. Paternal age 30 years. Maternal age 28 years | Selected birth defects Adjusted for paternal race and ethnicity, paternal education, maternal alcohol, maternal smoking, parity, earlier miscarriage, plurality, paternal drug used during pregnancy, use of ART, maternal BMI, folic acid use
| Medium |
Grewal et al. (2012), USA | Case control | 46 114 cases with birth defects | Paternal age: Nervous system anomalies: 38 years: AOR 1.05 (1.00–1.11) 42 years: AOR 1.10 (1.02–1.18) Limb anomalies: 38 years: AOR 1.06 (1.02–1.11) 42 years: AOR 1.11 (1.05–1.18) Integument anomalies: 38 years: AOR 1.05 (1.00–1.09) 42 years: AOR 1.10 (1.03–1.16) For fathers 29 years versus <29 years: Amniotic band syndrome: AOR 0.87 (0.78–0.97) Pyloric stenosis: AOR 0.93 (0.90–0.96) Anomalies of the great veins: AOR 0.93 (0.87–1.00)
| | | Medium |
Harville et al. (2007), Norway | Cohort study | 1431 cases | Paternal age: Cleft palate alone: 30–34 years: AOR 1.00 (0.76–1.31) 35–39 years: AOR 0.94 (0.68–1.30) ≥40 years: AOR 1.10 80.76–1.60)
| Paternal age 20–24 years 1.8 million controls
| | High |
Hook et al. (1981), USA | Cohort study | 551 cases 1952–1963 and 492 cases 1964–1976 | For 1952–1963 there was no significant paternal age effect (36.87 versus 36.82 years) For 1964–1976, paternal age was about half a year greater in cases than in controls (34.55 versus 34.09 years, P < 0.05)
| 418 017 births 1952–1963 418 848 births 1964–1976
| | Medium |
Hook and Cross (1982), USA | Case control | 98 cases of prenatally detected trisomy 21 | Mean difference in paternal age 0.27 (−1.59 to +1.06) | 10 239 foetuses with normal karyotype | | Medium |
Hook and Regal (1984), USA | Case control | 2354 cases with trisomy 21, 116 cases with trisomy 13 (including cases prenatally diagnosed) | No effect of paternal age | Controls were from all live births the same year in New York State | | Low |
Kazaura and Lie (2002), Norway | Cohort study | 1 738 852 infants 1788 trisomy 21
| | None | | High |
Kazaura et al. (2004a), Norway | Cohort study | 291 cases with gastroschisis | Higher risk at young paternal age AOR 1.6 (1.0–2.4) per 10 year decrease in paternal age after adjustment for maternal age, but was not significant after adjustment for paternal year of birth, AOR per year of father’s age: 1.04 (0.99–1.08)
| >1.7 million controls | | High |
Kazaura et al. (2004b), Norway | Cohort study | 1 869 388 births, 42 813 infants with birth defects | Paternal age 45–49 years: CNS defects (not neural tube defects, anencephaly, spina bifida or hydrocephaly) AOR 2.5 (1.2–5.5) Paternal age 20–24 years: Anencephaly AOR 1.4 (1.1–1.8) Neural tube defects. AOR 1.3 (1.1–1.5) Cleft lip: AOR between 0.9–1.2 (NS) Any birth defects: AOR 1.0–1.1 (borderline significant)
| Paternal age 25–29 years | Any and selected birth defects Adjusted for maternal age, parity, maternity institution and year of birth
| High |
Lian et al. (1986), USA | Cohort study | 7490 infants with a major or serious birth defect | Paternal age ≥35 years versus <35 years: ASD: AOR 1.95 (significant) Paternal age ≥40 years versus <40 years: Any birth defect: AOR 1.20 (significant) VSD: AOR 1.69 (significant) Chondrodystrophy: AOR 13.32 (significant) Situs inversus: AOR 19.27 (significant) Paternal age ≥45 versus <45 years Cleft palate/lip: AOR 2.86 (significant) Trisomy 21: NS any age
| 333 624 live born control infants without defects | | Medium |
Lorda-Sanchez et al. (1998), Spain | Case control | 14 cases | Associated with increase in: Paternal age (34.5 ± 6.0 versus 29.6 ± 6.0), OR 1.11 (1.02–1.21) but NS after adjustment for maternal age and no of pregnancies
| 162 controls | Klippel–Trenaunay–Weber syndrome | Low |
Materna-Kiryluk et al. (2009), Polen | Cohort study | 8683 infants 0–2 years with birth defects | AOR (per five years increase in paternal age) Heart defects: AOR 1.05 (1.00–1.09) Cleft lip with or without cleft palate: AOR 1.11 (1.02–1.20) Hypospadia: AOR 1.11 (1.03–1.19) Gastroschisis: AOR 0.69 (0.54–0.90)
| 902 452 population | | High |
McIntosh et al. (1995), USA | Case control | 9431 cases with 22 different birth defects (Trisomy 21, n = 997, cleft palate, n = 1489)
| Neural tube defects Paternal age 40–44, >50 years AORs 1.6 and 2.3 (borderline significant) Reduction of upper limbs 35–39, 40–44 years AORs: 2.1 and 2.4 (significant) Trisomy 21: 40–44, 45–49, ≥50 years AORs 1.5 to 2.0 (significant) Cleft palate: AORs 0.8–1.5 (NS)
| 18 862 controls Paternal age 25–29 years
| | Medium |
Olshan et al. (1994), USA | Case control | 4110 cases with CHD | General increase by paternal age with trend analysis, NS per age group | 8220 controls Paternal age 25–29 years
| | Low |
Orioli et al. (1995), Italy | Case control | 78 cases with achondroplasia (AC) 64 cases with thanatophoric dysplasia (TD) 106 cases with osteogenesis imperfecta (OI)
| | 2 controls per cases Paternal age <30 years Maternal age >30 years
| Achondroplasia (AC), thanatophoric dysplasia (TD), osteogenesis imperfecta (OI), Stratified for maternal age > and <30 years
| Low |
Polednak (1976), USA | Cohort study | 897 orofacial clefts | | 776 642 population Maternal age 25–29 years
| Any and selected birth defects. Stratified for maternal age | Low |
Poletta et al. (2007), South America | Case control | 5128 cleft lip/palate, 1745 cleft palate | Among 3/11 strata (representing 50% of the cases) significant higher risk with paternal age, ORs between 1.42–3.56 | 3712 controls | Orofacial clefts, probably not adjusted for maternal age | Medium/low |
Riccardi et al. (1984), USA | Case series | 187 cases | Paternal age >35 years: 2-fold increase
| | | Low |
Roecker and Huether (1983), USA | Cohort study | 1244 cases | No paternal age effect | 1 672 210 controls | | Low |
Roth et al. (1983a), France | Case control | 118 cases | | 6656 prenatal diagnoses (amniocentesis) | | Low |
Roth et al. (1983b), France | | | | 2 controls per cases in study 2 | | Low |
Stene et al. (1977), Denmark | Case control | 224 cases | Increased risk of trisomy 21 with paternal age >55 years | 5619 controls | | Low |
Stene et al. (1981), Denmark | Case control | 117 cases | Increased risk of trisomy 21 by paternal age >41 years | 5014 prenatal diagnoses | | Low |
Su et al. (2015), China | Cohort study (Denmark) | 15 216 cases with CHDs | | 1 893 899 population Paternal age 25–29 years | CHDs Controlled for maternal age, family history of CHD, maternal infection, gender, parity, parental age difference
| High |
Takano et al. (1992), Japan | Cohort study | 26 cases | No significant effect of paternal age (P = 0.08) | Population controls | Neurofibromatosis | Low |
Tay et al. (1982), Singapore | Case control | 100 cases | No effect of paternal age | 100 controls | Congenital heart disease | Low |
Tellier et al. (1996), France | Cohort study | 41 cases with CHARGE | | Control population not described | CHARGE malformations (coloboma, heart malformation, choanal atresia, retarded growth, genital hypoplasia, ear anomalies and deafness etc) No difference in maternal age
| Low |
Urhoj et al. (2015), Denmark | Cohort study | 10 817 cases with musculoskeletal congenital abnormalities | | 1 605 885 population | Musculoskeletal congenital abnormalities Adjusted for maternal age, year of birth, ethnicity and education
| High |
Vashist et al. (2011), India | Case series | 200 cases with trisomy 21 | Association with paternal age (correlation coeff (r) = 0.04, maternal age constant) | Mean paternal age 31.5 years | Trisomy 21 | Low |
Wolf (1963), USA | Case control | 411 cases with cleft lip and palate | A significant paternal age effect (P < 0.05) | 411 controls | | Low |
Yang et al. (2007), Canada | Cohort study | 77 514 cases with birth defects (Trisomy, n = 13 078, cleft palate, n = 6049)
| Paternal age 35–39, 40–44, 45–49, ≥50 years Any birth defects: AORs: 1.04–1.15 (significant), test for trend P = 0.015 Trisomy 21: AORs 1.19–1.45 (significant), test for trend P < 0.01 Cleft palate: AOR 0.89–1.23 (NS for any age group)
| 5 213 248 population Paternal age 25–29 years
| Any and selected birth defects Advanced paternal age was associated with: Any birth defects, heart defects, tracheo-oesophageal fistula, oesophageal atresia, musculoskeletal/ integumental anomalies, trisomy 21 and other chromosomal anomalies Paternal age <25 years were associated with: Spina bifida/ meningocele, microcephalus, omphalocele/gastroschisis Adjusted for maternal age, race, education, marital status, parity, prenatal care, smoking, alcohol consumption in woman
| High |
Zhan et al. (1991), China | Case control | 497 cases with CHDs | Paternal age <25 years AOR:2.63 (2.12–3.27)
| 6222 controls Paternal age ≥25 years
| | Low |
Zhu et al. (2005b), USA and Denmark | Cohort study | | No overall effect for any birth defect Paternal age >50 years: Trisomy 21 AHR: 4.50 (1.0–20.39) Paternal age 35–39 years: Cleft palate: AHR 1.48 (1.02–2.15) Multiple syndromes, extremities, increased by age, test for trend P < 0.001–0.05
| 71 937 population Paternal age 20–29 years
| Any and selected birth defectsAdjusted for maternal age, parity, maternal and paternal income and education, sex of child and year of birth | High |
Figure 5
Forest plot describing the association between paternal age and risk for any birth defects in offspring.
Conclusion: Higher paternal age is probably associated with a small increase in birth defects. Moderate certainty of evidence (GRADE⊕⊕⊕○).
Congenital heart defects
Seven studies investigated the association between paternal age and CHDs (Supplementary Table SI, Table II). Five of these studies were high quality, one medium and one of low quality. All studies could be included in the meta-analysis. No significant association was identified between paternal age and CHD (pooled estimate 1.03, 95% CI 0.99–1.06) (Fig. 6).
Figure 6
Forest plot describing the association between paternal age and risk for CHDs in offspring,
Conclusion: Higher paternal age is probably associated with little or no difference in the risk of CHD. Moderate certainty of evidence (GRADE⊕⊕⊕○).
Orofacial clefts
We identified 13 studies, eight of high quality, three of medium quality and two of low quality, for an assessment of orofacial clefts (Supplementary Table SI, Table II). In addition, a systematic review/meta-analysis has analysed the influence of parental age on oral clefts (Herkrath et al., 2012). For paternal age, only two studies could be included in their meta-analysis. A paternal age of 40 years and above was associated with an increased risk of cleft palate (OR 1.58, 95% CI 1.15–2.17). We performed a meta-analysis including five studies (Fig. 7). No overall effect of increased paternal age on the incidence of orofacial clefts was found (pooled estimate 0.99, 95% CI 0.95–1.04) while an age of above 45 years was associated with a small but significant increase in orofacial clefts (pooled estimate 1.14, 95% CI 1.02–1.29 (Fig. 7).
Figure 7
Forest plot describing the association between paternal age and risk for orofacial clefts in offspring.
Conclusion: Paternal age above 45 years may be associated with a small increase in orofacial clefts. Low certainty of evidence (GRADE ⊕⊕○○).
Gastroschisis
Five studies assessed the risk of gastroschisis in association with paternal age, four of high and one of medium quality (Supplementary Table SI, Table II). All these five studies are included in the meta-analysis (Fig. 8). Overall, higher paternal age was not associated with the risk of gastroschisis (pooled estimate 0.88 95% CI 0.78–1.00) (Fig. 8). A significantly lower rate was observed in children whose fathers’ paternal ages were between 35 and 40 years, compared to a reference age of between 25 and 29 years (U-shaped association).
Figure 8
Forest plot describing the association between paternal age and risk for gastroschisis in offspring.
Conclusion: Children of fathers aged 35 to 40 years probably have a lower risk of gastroschisis than children of younger fathers.
Moderate certainty of evidence (GRADE⊕⊕⊕○).
Spina bifida
Five studies assessed the risk of spina bifida in association with paternal age, three of high and two of medium quality (Supplementary Table SI, Table II). All these five studies could be included in a meta-analysis. No overall higher risk of spina bifida was associated with increasing age (pooled estimate 0.97, 95% CI 0.90–1.04) (Fig. 9).
Figure 9
Forest plot describing the association between paternal age and risk for spina bifida in offspring.
Conclusion: Higher paternal age is probably associated with little or no difference in the risk of spina bifida. Moderate certainty of evidence (GRADE⊕⊕⊕○).
Chromosomal anomalies
Twenty-three studies of chromosomal anomalies were identified, most of them assessing trisomy 21 (Supplementary Table SI, Table II). Five of these studies were high-quality cohort studies, nine were medium and nine were low quality, mostly case control studies (Supplementary Table SV). Altogether these studies included more than 37 000 (37 513) children with trisomy 21. Six of the studies could be included in a meta-analysis (Fig. 10). The meta-analysis identified a small but significantly increased risk of trisomy 21 associated with paternal age (pooled estimate 1.13, 95% CI 1.05–1.23). The rate was significantly increased at ages 40 years and above (Fig. 10). For other aneuploidies (trisomy 13 and 18), one high quality study could not identify any increase by paternal age.
Figure 10
Forest plot describing the association between paternal age and risk for trisomy 21 in offspring.
Conclusion: Higher paternal age is probably associated with a small increase in the incidence of trisomy 21. Moderate certainty of evidence (GRADE⊕⊕⊕○).
Paternal age at childbirth and long-term outcomes for offspring
Morbidity and mortality
Twenty-two studies assessed the effect of paternal age on childhood morbidity including childhood cancer (13 studies), diabetes and obesity (three studies), developmental disturbances (one study) and mortality (five studies). In addition, one meta-analysis concentrated on the risk of leukaemia (Sergentanis et al., 2015).
Childhood cancer
We identified 13 studies, four of high quality, six of medium quality and three of low quality. They examined childhood cancer in general as well as haematological cancer and leukaemia, retinoblastoma, non-Hodgkin lymphoma, Wilm’s tumour and brain tumours in particular (Supplementary Table SI, Table III).
Table IIIStudies on the association of paternal age with childhood morbidity and mortality in offspring.
Author, year, country
. | Study design
. | Number of children
. | Result
. | Outcomes
. | Quality
. |
---|
Outcomes (Risk estimates)
. | Reference group/control
. |
---|
Meta-analysis n = 1 |
Sergentanis et al. (2015), Greece | Systematic review and meta-analysis | Paternal age as categorical variable: 34 case control studies and 4 cohort studies in systematic review As incremental variable: 9 case control studies and 3 cohort studies in systematic review Meta-analysis (incremental analysis): 8 case control studies and 2 cohort studies
| ALL: A 5 year increase in paternal age: RR 1.04 (1.00–1.08) ‘Oldest versus middle’: Increased risk in oldest fathers with RR 1.10 (1.02–1.19) ARR 1.09 (0.90–1.25) ‘Youngest versus middle age’: increased risk in youngest with RR 1.09 (1.00–1.20) ARR 1.10 (0.81–1.51) AML: No significant associations at incremental analysis or ‘oldest versus middle’ Increased risk in offspring from ‘younger fathers versus middle’ with pooled RR 1.28 (1.04–1.59) ARR 0.63 (0.33–1.20)
| Paternal age: ‘Older’: >35 years or >40 years ‘Younger’: <25 years
| Many studies in forest plots did not adjust for maternal age (RR), but sub-analyses regarding degree of adjustments were included (ARR) | Medium |
Original articles n = 22 |
Cardwell et al. (2005), UK Northern Ireland | Cohort study | | | Paternal age <25 years | | Medium |
Crump et al. (2012), Sweden | Cohort study | | Adjusted risk estimates not mentioned in text, no association, ptrend = 0.31 | Probably paternal age <20 years | | Medium |
Crump et al. (2015), Sweden | Cohort study | 2809 cases with brain Tumours 3 571 574 population (25–29år)
| | Paternal age 25–29 years | Children born 1973–2008 followed through 2010 (max age 38 years) Adjusted for maternal age, birth year, sex, foetal growth, parental country at birth, family history of brain-tumour, maternal education
| Medium |
DerKinderen et al. (1990), the NL | Cohort study | | | Paternal age 25–34 years | | Low |
Dockerty et al. (2001), UK | Case control | | Paternal age: Retinoblastoma: 40–45 years AOR 0.82 (95% CI 0.39–1.75) ≥45 years AOR 0.73 (95% CI 0.26–2.01) ALL: 40–44 years AOR 1.45 (95% CI 1.10–1.92), ≥45 years AOR 1.54 (95% CI 1.06–2.23)
| Paternal age 25–29 years | | Medium |
Eriksen et al. (2013), Norway | Cohort study | | | Paternal age <20 years | Male conscripts at 18–20 years, born 1967–1984 Overweight defined as BMI 25.0–29.9 kg/m2 Obesity defined as BMI > 30 kg/m2 Adjusted for birth order, birth years, birth season, maternal age, parity of mother, maternal marital status at birth, parental education level
| High |
Heck et al. (2012), USA, California | Case control | | | Paternal age 20–29 years | Children diagnosed with retinoblastoma 1988–2007, children up to 5 years Confounding variables in multivariate models were year of birth, paternal age, urban or rural county of residence, maternal race and maternal place of birth. No information about adjustment for maternal age
| Medium |
Iwayama et al. (2011), Japan | Cohort study | | Developmental delay AOR 2.25 (1.33–3.80) (36 cases) No word uttering AOR 2.29 (1.52–3.44) (60 cases) Lack of eye contact AOR 5.16 (1.92–13.8) (6 cases) Unable to walk with support AOR 1.51 (1.21–1.91) (230 cases)
| Paternal age was categorized: <20, 20–29, 30–39, 40–49 and ≥50 years. The younger category group was the reference group | Children attending child health check-up at age 12 months during 1987–2003 examining child growth and developmental delay. (Included in obstetric outcome, Table 1a) Adjusted for maternal age
| Low |
Johnson et al. (2009), USA | Case control | | | OR related to a 5-year increase in paternal age | Children 0–14 years diagnosed with cancer 1980–2004 Controls born 1970–2004 Adjusted for maternal age, sex, birth weight, gestational age, birth order, plurality, maternal race, birth year and state
| High |
Larfors et al. (2012), Sweden | Case control | | | Paternal age 20–34 years | Born 1932 or later, diagnosed with leukaemia (children and adult leukaemia) during 1962–2008 Adjusted for sex, Down syndrome and chromosomal aberrations, multiple birth, number of siblings, maternal/paternal age
| Medium |
Matsunaga et al. (1990), Japan | Case control | | | No specific control group | | Low |
Maule et al. (2007), Italy | Cohort study | | | 25–29 years | Children aged 1–5 years 1980–1997 Adjusted for sex, year of birth, paternal/maternal age
| Medium |
Miller et al. (2010), Finland | Cohort study | 10 965 population 318 cases/deaths
| | Paternal age 25–29 years | Mortality in offspring born in 1966 and followed to age 39 Adjusted for age of the other parent, subject age, parent social class, maternal parity
| Medium |
Mok et al. (2017), Denmark | Cohort study | | | Paternal age 25–29 years | Mortality in children born 1966–1998 and followed to their 15th or 40th birthday or until 2011 Article also in Table 2d: other psychiatric disorders Older paternal age not associated with premature mortality after adjustments except for risk of natural death linked with paternal age 45 years and over. Adjusted for other parent’s age, offspring age and sex
| Medium |
Stene et al. (2001), Norway | Cohort study | 1 382 602 population 1824 with DM type 1
| | Paternal age < 25 years | DM type 1 in children born 1974–1998, followed for maximum 15 years until 1989–1998 Adjusted for age group year of birth, maternal age, birth order
| High |
Teras et al. (2015), USA | Cohort study | | | Paternal age < 25 years | Haematological malignancies diagnosed 1992–2009 No clear linear trend in risk by paternal age Adjusted for age of the other parent and sex
| High |
Urhoj et al. (2014), Denmark | Cohort study | 10 855 cases 1 575 521 population
| | Reference group: Paternal age 30–34 years
| Mortality before the age of 5 years in children born 1978–2004 Paternal age associated with increased risk of dying in early childhood due to an excess risk of fatal congenital anomalies, malignancies and external causes. Adjusted for maternal age, parity, parental education, year of birth.
| High |
Urhoj et al. (2017b), Denmark | Cohort study | 3492 cases 1 904 363 population
| | Paternal age 30–34 years | Paternal age associated with risk of ALL with 13% higher HR for every 5 years increase in paternal age. No firm conclusions for other specific cancer types Adjusted for maternal age, child’s year of birth, parental educational levels, parental ethnic origin and maternal parity
| High |
Wunsch and Gourbin (2002), Hungary | Cohort study | 490 000 population 8300 cases/deaths
| | Paternal age 35–44 years | Live births and infant deaths from 1984–1988: Early neonatal: up to 7 days of life Neonatal: up to 28 days of life Post neonatal: 28 days to 1 year of life No adjustments described
| Low |
Yip et al. (2006), Sweden | Cohort study | | Paternal age >40 years: Retinoblastoma: AIRR 0.96 (0.47–1.97) Leukaemia AIRR 1.14 (0.85–1.53) CNS tumours AIRR 1.69 (1.21–2.35) Astrocytoma AIRR 1.95 (1.10–3.45) Wilm’s tumour AIRR 1.53 (0.89–2.65) Non-Hodgkin’s lymphoma >40 years AIRR 1.09 (0.55–2.16)
| Paternal age <25 years | | High |
Zhu et al. (2008), Denmark | Cohort study | 108 879 population 831 cases/deaths
| | Paternal age 25–29 years | Mortality in singletons born 1980–1966 followed up to 18 years Adjusted for maternal age and parity, parental education and income, parental country of origin and calendar period
| Medium |
Zorlu et al. (2002), Turkey | Case control | 116 cases with ALL 400 controls
| Paternal age: >40 years ALL AOR 3.30 (1.28–8.51)
| Paternal age < 40 years | Diagnosed with leukaemia in 1993–1996, aged 1–14 years. Adjusted for patients’ age No adjustments for maternal age (no relationship with maternal age and the risk of ALL was found)
| Low |
Author, year, country
. | Study design
. | Number of children
. | Result
. | Outcomes
. | Quality
. |
---|
Outcomes (Risk estimates)
. | Reference group/control
. |
---|
Meta-analysis n = 1 |
Sergentanis et al. (2015), Greece | Systematic review and meta-analysis | Paternal age as categorical variable: 34 case control studies and 4 cohort studies in systematic review As incremental variable: 9 case control studies and 3 cohort studies in systematic review Meta-analysis (incremental analysis): 8 case control studies and 2 cohort studies
| ALL: A 5 year increase in paternal age: RR 1.04 (1.00–1.08) ‘Oldest versus middle’: Increased risk in oldest fathers with RR 1.10 (1.02–1.19) ARR 1.09 (0.90–1.25) ‘Youngest versus middle age’: increased risk in youngest with RR 1.09 (1.00–1.20) ARR 1.10 (0.81–1.51) AML: No significant associations at incremental analysis or ‘oldest versus middle’ Increased risk in offspring from ‘younger fathers versus middle’ with pooled RR 1.28 (1.04–1.59) ARR 0.63 (0.33–1.20)
| Paternal age: ‘Older’: >35 years or >40 years ‘Younger’: <25 years
| Many studies in forest plots did not adjust for maternal age (RR), but sub-analyses regarding degree of adjustments were included (ARR) | Medium |
Original articles n = 22 |
Cardwell et al. (2005), UK Northern Ireland | Cohort study | | | Paternal age <25 years | | Medium |
Crump et al. (2012), Sweden | Cohort study | | Adjusted risk estimates not mentioned in text, no association, ptrend = 0.31 | Probably paternal age <20 years | | Medium |
Crump et al. (2015), Sweden | Cohort study | 2809 cases with brain Tumours 3 571 574 population (25–29år)
| | Paternal age 25–29 years | Children born 1973–2008 followed through 2010 (max age 38 years) Adjusted for maternal age, birth year, sex, foetal growth, parental country at birth, family history of brain-tumour, maternal education
| Medium |
DerKinderen et al. (1990), the NL | Cohort study | | | Paternal age 25–34 years | | Low |
Dockerty et al. (2001), UK | Case control | | Paternal age: Retinoblastoma: 40–45 years AOR 0.82 (95% CI 0.39–1.75) ≥45 years AOR 0.73 (95% CI 0.26–2.01) ALL: 40–44 years AOR 1.45 (95% CI 1.10–1.92), ≥45 years AOR 1.54 (95% CI 1.06–2.23)
| Paternal age 25–29 years | | Medium |
Eriksen et al. (2013), Norway | Cohort study | | | Paternal age <20 years | Male conscripts at 18–20 years, born 1967–1984 Overweight defined as BMI 25.0–29.9 kg/m2 Obesity defined as BMI > 30 kg/m2 Adjusted for birth order, birth years, birth season, maternal age, parity of mother, maternal marital status at birth, parental education level
| High |
Heck et al. (2012), USA, California | Case control | | | Paternal age 20–29 years | Children diagnosed with retinoblastoma 1988–2007, children up to 5 years Confounding variables in multivariate models were year of birth, paternal age, urban or rural county of residence, maternal race and maternal place of birth. No information about adjustment for maternal age
| Medium |
Iwayama et al. (2011), Japan | Cohort study | | Developmental delay AOR 2.25 (1.33–3.80) (36 cases) No word uttering AOR 2.29 (1.52–3.44) (60 cases) Lack of eye contact AOR 5.16 (1.92–13.8) (6 cases) Unable to walk with support AOR 1.51 (1.21–1.91) (230 cases)
| Paternal age was categorized: <20, 20–29, 30–39, 40–49 and ≥50 years. The younger category group was the reference group | Children attending child health check-up at age 12 months during 1987–2003 examining child growth and developmental delay. (Included in obstetric outcome, Table 1a) Adjusted for maternal age
| Low |
Johnson et al. (2009), USA | Case control | | | OR related to a 5-year increase in paternal age | Children 0–14 years diagnosed with cancer 1980–2004 Controls born 1970–2004 Adjusted for maternal age, sex, birth weight, gestational age, birth order, plurality, maternal race, birth year and state
| High |
Larfors et al. (2012), Sweden | Case control | | | Paternal age 20–34 years | Born 1932 or later, diagnosed with leukaemia (children and adult leukaemia) during 1962–2008 Adjusted for sex, Down syndrome and chromosomal aberrations, multiple birth, number of siblings, maternal/paternal age
| Medium |
Matsunaga et al. (1990), Japan | Case control | | | No specific control group | | Low |
Maule et al. (2007), Italy | Cohort study | | | 25–29 years | Children aged 1–5 years 1980–1997 Adjusted for sex, year of birth, paternal/maternal age
| Medium |
Miller et al. (2010), Finland | Cohort study | 10 965 population 318 cases/deaths
| | Paternal age 25–29 years | Mortality in offspring born in 1966 and followed to age 39 Adjusted for age of the other parent, subject age, parent social class, maternal parity
| Medium |
Mok et al. (2017), Denmark | Cohort study | | | Paternal age 25–29 years | Mortality in children born 1966–1998 and followed to their 15th or 40th birthday or until 2011 Article also in Table 2d: other psychiatric disorders Older paternal age not associated with premature mortality after adjustments except for risk of natural death linked with paternal age 45 years and over. Adjusted for other parent’s age, offspring age and sex
| Medium |
Stene et al. (2001), Norway | Cohort study | 1 382 602 population 1824 with DM type 1
| | Paternal age < 25 years | DM type 1 in children born 1974–1998, followed for maximum 15 years until 1989–1998 Adjusted for age group year of birth, maternal age, birth order
| High |
Teras et al. (2015), USA | Cohort study | | | Paternal age < 25 years | Haematological malignancies diagnosed 1992–2009 No clear linear trend in risk by paternal age Adjusted for age of the other parent and sex
| High |
Urhoj et al. (2014), Denmark | Cohort study | 10 855 cases 1 575 521 population
| | Reference group: Paternal age 30–34 years
| Mortality before the age of 5 years in children born 1978–2004 Paternal age associated with increased risk of dying in early childhood due to an excess risk of fatal congenital anomalies, malignancies and external causes. Adjusted for maternal age, parity, parental education, year of birth.
| High |
Urhoj et al. (2017b), Denmark | Cohort study | 3492 cases 1 904 363 population
| | Paternal age 30–34 years | Paternal age associated with risk of ALL with 13% higher HR for every 5 years increase in paternal age. No firm conclusions for other specific cancer types Adjusted for maternal age, child’s year of birth, parental educational levels, parental ethnic origin and maternal parity
| High |
Wunsch and Gourbin (2002), Hungary | Cohort study | 490 000 population 8300 cases/deaths
| | Paternal age 35–44 years | Live births and infant deaths from 1984–1988: Early neonatal: up to 7 days of life Neonatal: up to 28 days of life Post neonatal: 28 days to 1 year of life No adjustments described
| Low |
Yip et al. (2006), Sweden | Cohort study | | Paternal age >40 years: Retinoblastoma: AIRR 0.96 (0.47–1.97) Leukaemia AIRR 1.14 (0.85–1.53) CNS tumours AIRR 1.69 (1.21–2.35) Astrocytoma AIRR 1.95 (1.10–3.45) Wilm’s tumour AIRR 1.53 (0.89–2.65) Non-Hodgkin’s lymphoma >40 years AIRR 1.09 (0.55–2.16)
| Paternal age <25 years | | High |
Zhu et al. (2008), Denmark | Cohort study | 108 879 population 831 cases/deaths
| | Paternal age 25–29 years | Mortality in singletons born 1980–1966 followed up to 18 years Adjusted for maternal age and parity, parental education and income, parental country of origin and calendar period
| Medium |
Zorlu et al. (2002), Turkey | Case control | 116 cases with ALL 400 controls
| Paternal age: >40 years ALL AOR 3.30 (1.28–8.51)
| Paternal age < 40 years | Diagnosed with leukaemia in 1993–1996, aged 1–14 years. Adjusted for patients’ age No adjustments for maternal age (no relationship with maternal age and the risk of ALL was found)
| Low |
Table IIIStudies on the association of paternal age with childhood morbidity and mortality in offspring.
Author, year, country
. | Study design
. | Number of children
. | Result
. | Outcomes
. | Quality
. |
---|
Outcomes (Risk estimates)
. | Reference group/control
. |
---|
Meta-analysis n = 1 |
Sergentanis et al. (2015), Greece | Systematic review and meta-analysis | Paternal age as categorical variable: 34 case control studies and 4 cohort studies in systematic review As incremental variable: 9 case control studies and 3 cohort studies in systematic review Meta-analysis (incremental analysis): 8 case control studies and 2 cohort studies
| ALL: A 5 year increase in paternal age: RR 1.04 (1.00–1.08) ‘Oldest versus middle’: Increased risk in oldest fathers with RR 1.10 (1.02–1.19) ARR 1.09 (0.90–1.25) ‘Youngest versus middle age’: increased risk in youngest with RR 1.09 (1.00–1.20) ARR 1.10 (0.81–1.51) AML: No significant associations at incremental analysis or ‘oldest versus middle’ Increased risk in offspring from ‘younger fathers versus middle’ with pooled RR 1.28 (1.04–1.59) ARR 0.63 (0.33–1.20)
| Paternal age: ‘Older’: >35 years or >40 years ‘Younger’: <25 years
| Many studies in forest plots did not adjust for maternal age (RR), but sub-analyses regarding degree of adjustments were included (ARR) | Medium |
Original articles n = 22 |
Cardwell et al. (2005), UK Northern Ireland | Cohort study | | | Paternal age <25 years | | Medium |
Crump et al. (2012), Sweden | Cohort study | | Adjusted risk estimates not mentioned in text, no association, ptrend = 0.31 | Probably paternal age <20 years | | Medium |
Crump et al. (2015), Sweden | Cohort study | 2809 cases with brain Tumours 3 571 574 population (25–29år)
| | Paternal age 25–29 years | Children born 1973–2008 followed through 2010 (max age 38 years) Adjusted for maternal age, birth year, sex, foetal growth, parental country at birth, family history of brain-tumour, maternal education
| Medium |
DerKinderen et al. (1990), the NL | Cohort study | | | Paternal age 25–34 years | | Low |
Dockerty et al. (2001), UK | Case control | | Paternal age: Retinoblastoma: 40–45 years AOR 0.82 (95% CI 0.39–1.75) ≥45 years AOR 0.73 (95% CI 0.26–2.01) ALL: 40–44 years AOR 1.45 (95% CI 1.10–1.92), ≥45 years AOR 1.54 (95% CI 1.06–2.23)
| Paternal age 25–29 years | | Medium |
Eriksen et al. (2013), Norway | Cohort study | | | Paternal age <20 years | Male conscripts at 18–20 years, born 1967–1984 Overweight defined as BMI 25.0–29.9 kg/m2 Obesity defined as BMI > 30 kg/m2 Adjusted for birth order, birth years, birth season, maternal age, parity of mother, maternal marital status at birth, parental education level
| High |
Heck et al. (2012), USA, California | Case control | | | Paternal age 20–29 years | Children diagnosed with retinoblastoma 1988–2007, children up to 5 years Confounding variables in multivariate models were year of birth, paternal age, urban or rural county of residence, maternal race and maternal place of birth. No information about adjustment for maternal age
| Medium |
Iwayama et al. (2011), Japan | Cohort study | | Developmental delay AOR 2.25 (1.33–3.80) (36 cases) No word uttering AOR 2.29 (1.52–3.44) (60 cases) Lack of eye contact AOR 5.16 (1.92–13.8) (6 cases) Unable to walk with support AOR 1.51 (1.21–1.91) (230 cases)
| Paternal age was categorized: <20, 20–29, 30–39, 40–49 and ≥50 years. The younger category group was the reference group | Children attending child health check-up at age 12 months during 1987–2003 examining child growth and developmental delay. (Included in obstetric outcome, Table 1a) Adjusted for maternal age
| Low |
Johnson et al. (2009), USA | Case control | | | OR related to a 5-year increase in paternal age | Children 0–14 years diagnosed with cancer 1980–2004 Controls born 1970–2004 Adjusted for maternal age, sex, birth weight, gestational age, birth order, plurality, maternal race, birth year and state
| High |
Larfors et al. (2012), Sweden | Case control | | | Paternal age 20–34 years | Born 1932 or later, diagnosed with leukaemia (children and adult leukaemia) during 1962–2008 Adjusted for sex, Down syndrome and chromosomal aberrations, multiple birth, number of siblings, maternal/paternal age
| Medium |
Matsunaga et al. (1990), Japan | Case control | | | No specific control group | | Low |
Maule et al. (2007), Italy | Cohort study | | | 25–29 years | Children aged 1–5 years 1980–1997 Adjusted for sex, year of birth, paternal/maternal age
| Medium |
Miller et al. (2010), Finland | Cohort study | 10 965 population 318 cases/deaths
| | Paternal age 25–29 years | Mortality in offspring born in 1966 and followed to age 39 Adjusted for age of the other parent, subject age, parent social class, maternal parity
| Medium |
Mok et al. (2017), Denmark | Cohort study | | | Paternal age 25–29 years | Mortality in children born 1966–1998 and followed to their 15th or 40th birthday or until 2011 Article also in Table 2d: other psychiatric disorders Older paternal age not associated with premature mortality after adjustments except for risk of natural death linked with paternal age 45 years and over. Adjusted for other parent’s age, offspring age and sex
| Medium |
Stene et al. (2001), Norway | Cohort study | 1 382 602 population 1824 with DM type 1
| | Paternal age < 25 years | DM type 1 in children born 1974–1998, followed for maximum 15 years until 1989–1998 Adjusted for age group year of birth, maternal age, birth order
| High |
Teras et al. (2015), USA | Cohort study | | | Paternal age < 25 years | Haematological malignancies diagnosed 1992–2009 No clear linear trend in risk by paternal age Adjusted for age of the other parent and sex
| High |
Urhoj et al. (2014), Denmark | Cohort study | 10 855 cases 1 575 521 population
| | Reference group: Paternal age 30–34 years
| Mortality before the age of 5 years in children born 1978–2004 Paternal age associated with increased risk of dying in early childhood due to an excess risk of fatal congenital anomalies, malignancies and external causes. Adjusted for maternal age, parity, parental education, year of birth.
| High |
Urhoj et al. (2017b), Denmark | Cohort study | 3492 cases 1 904 363 population
| | Paternal age 30–34 years | Paternal age associated with risk of ALL with 13% higher HR for every 5 years increase in paternal age. No firm conclusions for other specific cancer types Adjusted for maternal age, child’s year of birth, parental educational levels, parental ethnic origin and maternal parity
| High |
Wunsch and Gourbin (2002), Hungary | Cohort study | 490 000 population 8300 cases/deaths
| | Paternal age 35–44 years | Live births and infant deaths from 1984–1988: Early neonatal: up to 7 days of life Neonatal: up to 28 days of life Post neonatal: 28 days to 1 year of life No adjustments described
| Low |
Yip et al. (2006), Sweden | Cohort study | | Paternal age >40 years: Retinoblastoma: AIRR 0.96 (0.47–1.97) Leukaemia AIRR 1.14 (0.85–1.53) CNS tumours AIRR 1.69 (1.21–2.35) Astrocytoma AIRR 1.95 (1.10–3.45) Wilm’s tumour AIRR 1.53 (0.89–2.65) Non-Hodgkin’s lymphoma >40 years AIRR 1.09 (0.55–2.16)
| Paternal age <25 years | | High |
Zhu et al. (2008), Denmark | Cohort study | 108 879 population 831 cases/deaths
| | Paternal age 25–29 years | Mortality in singletons born 1980–1966 followed up to 18 years Adjusted for maternal age and parity, parental education and income, parental country of origin and calendar period
| Medium |
Zorlu et al. (2002), Turkey | Case control | 116 cases with ALL 400 controls
| Paternal age: >40 years ALL AOR 3.30 (1.28–8.51)
| Paternal age < 40 years | Diagnosed with leukaemia in 1993–1996, aged 1–14 years. Adjusted for patients’ age No adjustments for maternal age (no relationship with maternal age and the risk of ALL was found)
| Low |
Author, year, country
. | Study design
. | Number of children
. | Result
. | Outcomes
. | Quality
. |
---|
Outcomes (Risk estimates)
. | Reference group/control
. |
---|
Meta-analysis n = 1 |
Sergentanis et al. (2015), Greece | Systematic review and meta-analysis | Paternal age as categorical variable: 34 case control studies and 4 cohort studies in systematic review As incremental variable: 9 case control studies and 3 cohort studies in systematic review Meta-analysis (incremental analysis): 8 case control studies and 2 cohort studies
| ALL: A 5 year increase in paternal age: RR 1.04 (1.00–1.08) ‘Oldest versus middle’: Increased risk in oldest fathers with RR 1.10 (1.02–1.19) ARR 1.09 (0.90–1.25) ‘Youngest versus middle age’: increased risk in youngest with RR 1.09 (1.00–1.20) ARR 1.10 (0.81–1.51) AML: No significant associations at incremental analysis or ‘oldest versus middle’ Increased risk in offspring from ‘younger fathers versus middle’ with pooled RR 1.28 (1.04–1.59) ARR 0.63 (0.33–1.20)
| Paternal age: ‘Older’: >35 years or >40 years ‘Younger’: <25 years
| Many studies in forest plots did not adjust for maternal age (RR), but sub-analyses regarding degree of adjustments were included (ARR) | Medium |
Original articles n = 22 |
Cardwell et al. (2005), UK Northern Ireland | Cohort study | | | Paternal age <25 years | | Medium |
Crump et al. (2012), Sweden | Cohort study | | Adjusted risk estimates not mentioned in text, no association, ptrend = 0.31 | Probably paternal age <20 years | | Medium |
Crump et al. (2015), Sweden | Cohort study | 2809 cases with brain Tumours 3 571 574 population (25–29år)
| | Paternal age 25–29 years | Children born 1973–2008 followed through 2010 (max age 38 years) Adjusted for maternal age, birth year, sex, foetal growth, parental country at birth, family history of brain-tumour, maternal education
| Medium |
DerKinderen et al. (1990), the NL | Cohort study | | | Paternal age 25–34 years | | Low |
Dockerty et al. (2001), UK | Case control | | Paternal age: Retinoblastoma: 40–45 years AOR 0.82 (95% CI 0.39–1.75) ≥45 years AOR 0.73 (95% CI 0.26–2.01) ALL: 40–44 years AOR 1.45 (95% CI 1.10–1.92), ≥45 years AOR 1.54 (95% CI 1.06–2.23)
| Paternal age 25–29 years | | Medium |
Eriksen et al. (2013), Norway | Cohort study | | | Paternal age <20 years | Male conscripts at 18–20 years, born 1967–1984 Overweight defined as BMI 25.0–29.9 kg/m2 Obesity defined as BMI > 30 kg/m2 Adjusted for birth order, birth years, birth season, maternal age, parity of mother, maternal marital status at birth, parental education level
| High |
Heck et al. (2012), USA, California | Case control | | | Paternal age 20–29 years | Children diagnosed with retinoblastoma 1988–2007, children up to 5 years Confounding variables in multivariate models were year of birth, paternal age, urban or rural county of residence, maternal race and maternal place of birth. No information about adjustment for maternal age
| Medium |
Iwayama et al. (2011), Japan | Cohort study | | Developmental delay AOR 2.25 (1.33–3.80) (36 cases) No word uttering AOR 2.29 (1.52–3.44) (60 cases) Lack of eye contact AOR 5.16 (1.92–13.8) (6 cases) Unable to walk with support AOR 1.51 (1.21–1.91) (230 cases)
| Paternal age was categorized: <20, 20–29, 30–39, 40–49 and ≥50 years. The younger category group was the reference group | Children attending child health check-up at age 12 months during 1987–2003 examining child growth and developmental delay. (Included in obstetric outcome, Table 1a) Adjusted for maternal age
| Low |
Johnson et al. (2009), USA | Case control | | | OR related to a 5-year increase in paternal age | Children 0–14 years diagnosed with cancer 1980–2004 Controls born 1970–2004 Adjusted for maternal age, sex, birth weight, gestational age, birth order, plurality, maternal race, birth year and state
| High |
Larfors et al. (2012), Sweden | Case control | | | Paternal age 20–34 years | Born 1932 or later, diagnosed with leukaemia (children and adult leukaemia) during 1962–2008 Adjusted for sex, Down syndrome and chromosomal aberrations, multiple birth, number of siblings, maternal/paternal age
| Medium |
Matsunaga et al. (1990), Japan | Case control | | | No specific control group | | Low |
Maule et al. (2007), Italy | Cohort study | | | 25–29 years | Children aged 1–5 years 1980–1997 Adjusted for sex, year of birth, paternal/maternal age
| Medium |
Miller et al. (2010), Finland | Cohort study | 10 965 population 318 cases/deaths
| | Paternal age 25–29 years | Mortality in offspring born in 1966 and followed to age 39 Adjusted for age of the other parent, subject age, parent social class, maternal parity
| Medium |
Mok et al. (2017), Denmark | Cohort study | | | Paternal age 25–29 years | Mortality in children born 1966–1998 and followed to their 15th or 40th birthday or until 2011 Article also in Table 2d: other psychiatric disorders Older paternal age not associated with premature mortality after adjustments except for risk of natural death linked with paternal age 45 years and over. Adjusted for other parent’s age, offspring age and sex
| Medium |
Stene et al. (2001), Norway | Cohort study | 1 382 602 population 1824 with DM type 1
| | Paternal age < 25 years | DM type 1 in children born 1974–1998, followed for maximum 15 years until 1989–1998 Adjusted for age group year of birth, maternal age, birth order
| High |
Teras et al. (2015), USA | Cohort study | | | Paternal age < 25 years | Haematological malignancies diagnosed 1992–2009 No clear linear trend in risk by paternal age Adjusted for age of the other parent and sex
| High |
Urhoj et al. (2014), Denmark | Cohort study | 10 855 cases 1 575 521 population
| | Reference group: Paternal age 30–34 years
| Mortality before the age of 5 years in children born 1978–2004 Paternal age associated with increased risk of dying in early childhood due to an excess risk of fatal congenital anomalies, malignancies and external causes. Adjusted for maternal age, parity, parental education, year of birth.
| High |
Urhoj et al. (2017b), Denmark | Cohort study | 3492 cases 1 904 363 population
| | Paternal age 30–34 years | Paternal age associated with risk of ALL with 13% higher HR for every 5 years increase in paternal age. No firm conclusions for other specific cancer types Adjusted for maternal age, child’s year of birth, parental educational levels, parental ethnic origin and maternal parity
| High |
Wunsch and Gourbin (2002), Hungary | Cohort study | 490 000 population 8300 cases/deaths
| | Paternal age 35–44 years | Live births and infant deaths from 1984–1988: Early neonatal: up to 7 days of life Neonatal: up to 28 days of life Post neonatal: 28 days to 1 year of life No adjustments described
| Low |
Yip et al. (2006), Sweden | Cohort study | | Paternal age >40 years: Retinoblastoma: AIRR 0.96 (0.47–1.97) Leukaemia AIRR 1.14 (0.85–1.53) CNS tumours AIRR 1.69 (1.21–2.35) Astrocytoma AIRR 1.95 (1.10–3.45) Wilm’s tumour AIRR 1.53 (0.89–2.65) Non-Hodgkin’s lymphoma >40 years AIRR 1.09 (0.55–2.16)
| Paternal age <25 years | | High |
Zhu et al. (2008), Denmark | Cohort study | 108 879 population 831 cases/deaths
| | Paternal age 25–29 years | Mortality in singletons born 1980–1966 followed up to 18 years Adjusted for maternal age and parity, parental education and income, parental country of origin and calendar period
| Medium |
Zorlu et al. (2002), Turkey | Case control | 116 cases with ALL 400 controls
| Paternal age: >40 years ALL AOR 3.30 (1.28–8.51)
| Paternal age < 40 years | Diagnosed with leukaemia in 1993–1996, aged 1–14 years. Adjusted for patients’ age No adjustments for maternal age (no relationship with maternal age and the risk of ALL was found)
| Low |
Five studies assessed the effect of paternal age on the incidence of retinoblastoma. Only one study adjusted for maternal age (Yip et al., 2006), and did not report an association between paternal age and retinoblastoma.
In addition, in one systematic review/meta-analysis, the effect of paternal age on the risk of childhood leukaemia was assessed. This showed that higher paternal age was associated with an increased risk of childhood acute lymphoblastic leukaemia (ALL) (RR 1.05, 95% CI 1.01–1.10, per year increments: RR 1.04, 95% CI 1.00–1.08) (Sergentanis et al., 2015).
Two studies adjusted for maternal age and could be included in a meta-analysis (Fig. 11). No overall higher risk of ALL was associated with increasing age (pooled estimate 1.08, 95% CI 0.96–1.21).
Figure 11
Forest plot describing the association between paternal age and risk for acute lymphoblastic leukaemia in the offspring.
Conclusion: Higher paternal age is probably associated with little or no difference in the risk of ALL. Moderate certainty of evidence (GRADE⊕⊕⊕○). Higher paternal age may be associated with little or no difference in the risk of other childhood cancers. Low certainty of evidence (GRADE⊕⊕○○).
Diabetes mellitus type 1 and obesity
Two cohort studies concentrated on paternal age and diabetes mellitus (DM) type 1, and one study on overweight and obesity. Two of these studies were of high quality and one of medium quality (Supplementary Table SI, Table III). In both studies concerning DM, adjustments were made for maternal age. One study (Cardwell et al., 2005) reported an association with paternal age, and the other (Stene et al., 2001) found that paternal age was not significantly associated with DM type 1. One study associated an increased risk of obesity with paternal age > 50 years (Eriksen et al., 2013).
Conclusion: It is uncertain whether paternal age is associated with an increased risk of DM type 1 and obesity in offspring. Very low certainty of evidence (GRADE⊕○○○).
Mortality
Infant mortality during the first year of life and the possible effects of paternal age were studied by Wunsch and Gourbin (2002), while Urhoj et al. (2014) looked into mortality before the age of 5 years. Three studies concentrated on mortality up to 18, 39, and 40 years, respectively (Zhu et al., 2008; Miller et al., 2010; Mok et al., 2017) (Supplementary Table SI, Table III). In all studies, except Wunsch and Gourbin (2002), adjustments were made for maternal age. These four studies also reported an association of mortality with higher paternal age. It was not possible to do a meta-analysis because of different length of follow-up in the studies.
Conclusion: Higher paternal age may be associated with a small increase in risk of mortality. Low certainty of evidence (GRADE ⊕⊕○○).
Psychiatric diseases/disorders in offspring of older fathers
Autism and ASDs
Two meta-analyses (Hultman et al., 2011; Wu et al., 2017) and 28 original studies assessed the effect of paternal age on autism and ASD (Supplementary Table SI, Table IV). The original articles included 15 cohort studies and 13 case control studies. Five studies were of high quality, 16 of medium quality and seven of low quality. The systematic review/meta-analysis by Hultman et al. (2011) included 12 studies from seven different countries. The pooled estimates for autism and ASD were for offspring of fathers between 40 and 49 years old 1.78 (95% CI 1.52–2.07), and for offspring of fathers ≥50 years old 2.46 (95% CI 2.20–2.76). In the meta-analysis by Wu et al. (2017) including 27 studies, a significant association between paternal age and the risk of autism in offspring was found (AOR 1.55, 95% CI 1.39–1.73). We included 16 studies in our meta-analysis (Fig. 12). All of these studies adjusted for maternal age. It was observed that there was a higher risk of autism/ASD with increasing paternal age (pooled estimate 1.25, 95% CI 1.20–1.30).
Table IVStudies on the association of paternal age with autism/ASDs in offspring.
Author, year, country
. | Study design
. | Number of children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Adjustments
. |
---|
Outcome
. | Reference group/control
. |
---|
Systematic review and meta-analysis n = 2 |
Hultman et al. (2011), Sweden | | 11 studies (including 12 cohorts) with paternal age as exposure | Pooled estimates: 30–39 years 1.22 (1.05–1.42) 40–49 years 1.78 (1.52–2.07) ≥50 years 2.46 (2.20–2.76)
| Paternal age ≤29 years | Increased risk of autism with increased paternal age | Medium |
Wu et al. (2017), China | Systematic review and meta-analysis | 27 studies (6 cohort and 21 case control studies) with paternal age as exposure | | Reference point: Midpoint paternal age -age not mentioned
| Compared to reference point, lower paternal age was associated with reduced risk and increased paternal age was associated with increased risk of autism | Medium |
Original articles n = 28 |
Ben Itzchak et al. (2011), Israel | Cohort study | | Paternal age in a cohort with ASD. No risk estimate. | Paternal age 20–29 years | The percentage of fathers in the older age (30–40 years) was significantly higher in the ASD cohort compared to the Israeli newborn data (P < 0,01) | Low |
Bilder et al. (2009), USA | Case control | 132 cases with ASD 13 200 controls
| Paternal age: OR 1.28 (0.54–3.03)
| Paternal age 30–39 years | | Low |
Buizer-Voskamp et al. (2011), The Netherlands | Case control | | | Paternal age 25–29 years | Adjusted for maternal age <30 years and >30 years, ethnic background and average income of the residential area | Medium |
Burd et al. (1999a), USA | Case control study | 78 cases of autism 390 controls
| | Paternal age <20 or >30, 20–30 years
| | Low |
Byars and Boomsma (2016), Denmark | Cohort study | | Paternal age: 26–30 years AHR 0.92 (0.86–0.98) 35–39 years AHR 1.10 (1.03–1.18) 40–44 years AHR 1.19 (1.06–1.33) 45–60 years AHR 1.2 (1.04–1.49)
| Paternal age 31–34 years | Adjusted for other parent’s age (see STable I) | Medium |
Croen et al. (2007), USA | Case control | 593 cases with autism 132 251 population
| Paternal age: 35–39 years AOR 1.38 (1.04–1.84) ≥40 years AOR 1.52 (1.10–2.10) With each 10 year increase in paternal age ARR 1.34 (1.06–1.69)
| Paternal age 25–29 years | Adjusted for maternal age, birth order, gender, date of birth, parental educational level, ethnicity | Medium |
D’Onofrio et al. (2014), Sweden | Cohort study | | | Paternal age 20–24 years | Adjusted for maternal age, sex, year of birth, parental education, history of psychiatric hospitalization | High |
Durkin et al. (2008), USA | Cohort study | 1251 cases with autism 253 347 population
| | Paternal age 25–29 years | Adjusted for maternal age, birth order, gender, maternal education, ethnicity, multiple birth, gestational age, BW for gestational age | High |
Frans et al. (2013), Sweden | Case control | 5936 cases with autism 30 923 controls
| Paternal age: 45–49 years AOR 1.85 (1.47–2.31) ≥50 years AOR 2.23 (1.59–3.12) With each 10 years RR 1.25 (95% CI 1.17, 1.31)
| Paternal age 20–24 years | Adjusted for maternal age, birth year, gender, family history, educational level, country | Medium |
Grether et al. (2009), USA | Cohort study | 23 311 cases with autism 7 550 026 population | Paternal age: 50–54 years AOR 1.53 (1.32–1.77) 60–64 years AOR 2.05 (1.38–3.05) With each 10 year increase in paternal age (15–64 years) ARR 1.22 (1.18, 1.25)
| Paternal age 25–29 years | Adjusted for maternal age, child’s sex, birth weight, ethnicity, education, parity, gestational age, delivery method, birth year | High |
Hultman et al. (2011), Sweden | Cohort study | 883 cases with autism 1 075 588 population | Paternal age: 30–39 years AOR 1.19 (1.00–1.42) 40–49 years AOR 1.42 (1.07–1.87) ≥50 years AOR 2.21 (1.26–3.88) ≥55 years AOR 4.36 (2.09–9.09) With each 10 year increase in paternal age RR 1.21 (1.10, 1.34)
| Paternal age <29 years | Adjusted for maternal age, maternal country of birth, birth weight, maternal history of psychiatric illness, paternal country of birth, paternal history of psychiatric illness, BW, being small/large for gestational age, foetal distress, SES, birth order, year of birth of the offspring | Medium |
Idring et al. (2014), Sweden | Cohort study | 4746 cases with ASD 417 303 population
| Paternal age: 25–28 years AOR 0.93 (0.90–0.96) 35–39 years AOR 1.07 (1.04–1.10) 55–59 years AOR 1.39 (1.29–1.50)
| Paternal age 32 years | Adjusted for maternal age (using generalized additive models - GAMs), birth year, sex, parity, parental psychiatric history, occupational class, family income, maternal region of birth | High |
King et al. (2009), USA | Cohort study | 18 731 cases with autism 4 906 926 population
| | Paternal age <30 years | | Medium |
Lampi et al. (2013), Finland | Case control | 4713 cases with ASD 1132 with childhood autism 1785 with Asperger’s syndrome 1796 with pervasive development disorder (PDD) 18 777 controls
| Paternal age: Autism: 40–49 years AOR 1.6 (1.1–2.3) Asperger: 40–49 years AOR 1.1 (0.5–2.2) PDD: 40–49 years AOR 1.6 (0.8–3.2)
| Paternal age 25–29 years | Adjusted for maternal age, number of previous births, weight for gestational age, intellectual disability, maternal SES, paternal psychiatric history. | Medium |
Larsson et al. (2005), Denmark | Case control | 698 cases with autism 17 450 controls
| | Paternal age 25–29 years | Adjusted for perinatal factors, maternal age, parental psychiatric history, socio-economic characteristics | Medium |
Lauritsen et al. (2005) Denmark | Cohort study | 818 cases with autism 943 664 population
| | Paternal age 25–29 years | Adjusted for maternal age, gender, calendar year of diagnosis, paternal history of psychiatric disease, parental country of birth | Medium |
Lundstrom et al. (2010), Sweden | Cohort (twin cohort) - Sweden and UK | Sweden: 164 cases with ASD 11 122 population UK: 66 cases with ASD 13 524 population
| Paternal age in Sweden: 45–50 years AOR 1.90 (1.73–4.92) ≥51 years AOR 3.37 (1.02–11.14) Paternal age in UK: 45–49 years AOR 1.66 (0.47–5.82) ≥51 years AOR 3.59 (0.37–34.46)
| Paternal age 25–34 years | | Medium |
Maimburg and Vaeth (2006), Denmark | Case control | | | Paternal age 25–29 years | Adjusted for maternal age, maternal citizenship, BW, gestational age, Apgar score, birth defect, irregular foetal position | Medium |
Mamidala et al. (2013), India | Case control | 471 cases with ASD471 controls | | Paternal age <30 years | Adjusted for maternal age, gender, year of birth | Medium |
Parner et al. (2012), Denmark | Cohort study (sibling design) | 9556 cases with ASD 1 311 736 children
| | Paternal age <35 years | Combinations of parents’ ages: for mothers younger than 35 years, the risk of ASD increased with increasing father’s age group. Adjusted for gestational age, birth weight, birth order, sex, parental psychiatric history at birth | Medium |
Quinlan et al. (2015), USA (New York) | Cohort study | 1589 cases with ASD 927 003 population
| | Paternal age <25 years | Adjusted for parity, sex, race and ethnicity, gestational age, maternal metabolic risk factor, SGA. Not precise whether adjusted for maternal age | Medium |
Reichenberg et al. (2006), Israel | Cohort study | 319 cases with ASD 132 271 population
| | Paternal age 15–29 years | Adjusted for year of birth, SES and maternal age | Medium |
Sandin et al. (2016), Scandinavia (Danmark, Norge, Sweden), Western Australia and Israel | Cohort study | 30 902 cases with ASD 5 776 794 population
| Paternal age and risk for ASD: <20 years ARR 1.08 (0.92–1.27) 30–39 years ARR 1.05 (1.02–1.08) 40–49 years ARR 1.28 (1.22–1.34) ≥50 years ARR 1.64 (1.66–1.85)
| Paternal age 20–29 years | Joint effect of maternal and paternal age with increasing risk for couples with increasing differences in parental age. Adjusted for site (country), sex, birth year, maternal age
| High |
Sasanfar et al. (2010), Iran | Case control study | 179 cases with ASD 1611 controls
| | Cohort study: Paternal age 25–29 years Case control study: Paternal age 25–29 years
| Adjusted for parental education, birth order, sex, consanguinity, urbanism and province. Not precise whether adjusted for maternal age | Low |
Shelton et al. (2010), USA | Cohort study | 4 947 935 population 12 159 cases with autism
| | Paternal age 25–29 years | Adjusted for maternal age, parents race/ethnicity, year of birth, insurance type, parental education | Medium |
Tsuchiya et al. (2008), Japan | Case control | | Paternal age: 29–32 years: AOR 2.28 (1.02–5.11) ≥33 years: AOR 3.09 (1.17–8.16) Paternal age as a continuous variable: AOR 2.54 (0.96–6.72)
| Paternal age <29 years | | Low |
van Balkom et al. (2012), Aruba, The Netherlands | Case control | 95 cases with ASD 347 controls
| | Paternal age <30 years | Adjusted for maternal age and PTB | Low |
Zhang et al. (2010), China | Case control | 95 cases with autism 95 controls
| | Paternal age <30 years | Adjusted for paternal age, gender and birth year. No adjustments for maternal age | Low |
Author, year, country
. | Study design
. | Number of children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Adjustments
. |
---|
Outcome
. | Reference group/control
. |
---|
Systematic review and meta-analysis n = 2 |
Hultman et al. (2011), Sweden | | 11 studies (including 12 cohorts) with paternal age as exposure | Pooled estimates: 30–39 years 1.22 (1.05–1.42) 40–49 years 1.78 (1.52–2.07) ≥50 years 2.46 (2.20–2.76)
| Paternal age ≤29 years | Increased risk of autism with increased paternal age | Medium |
Wu et al. (2017), China | Systematic review and meta-analysis | 27 studies (6 cohort and 21 case control studies) with paternal age as exposure | | Reference point: Midpoint paternal age -age not mentioned
| Compared to reference point, lower paternal age was associated with reduced risk and increased paternal age was associated with increased risk of autism | Medium |
Original articles n = 28 |
Ben Itzchak et al. (2011), Israel | Cohort study | | Paternal age in a cohort with ASD. No risk estimate. | Paternal age 20–29 years | The percentage of fathers in the older age (30–40 years) was significantly higher in the ASD cohort compared to the Israeli newborn data (P < 0,01) | Low |
Bilder et al. (2009), USA | Case control | 132 cases with ASD 13 200 controls
| Paternal age: OR 1.28 (0.54–3.03)
| Paternal age 30–39 years | | Low |
Buizer-Voskamp et al. (2011), The Netherlands | Case control | | | Paternal age 25–29 years | Adjusted for maternal age <30 years and >30 years, ethnic background and average income of the residential area | Medium |
Burd et al. (1999a), USA | Case control study | 78 cases of autism 390 controls
| | Paternal age <20 or >30, 20–30 years
| | Low |
Byars and Boomsma (2016), Denmark | Cohort study | | Paternal age: 26–30 years AHR 0.92 (0.86–0.98) 35–39 years AHR 1.10 (1.03–1.18) 40–44 years AHR 1.19 (1.06–1.33) 45–60 years AHR 1.2 (1.04–1.49)
| Paternal age 31–34 years | Adjusted for other parent’s age (see STable I) | Medium |
Croen et al. (2007), USA | Case control | 593 cases with autism 132 251 population
| Paternal age: 35–39 years AOR 1.38 (1.04–1.84) ≥40 years AOR 1.52 (1.10–2.10) With each 10 year increase in paternal age ARR 1.34 (1.06–1.69)
| Paternal age 25–29 years | Adjusted for maternal age, birth order, gender, date of birth, parental educational level, ethnicity | Medium |
D’Onofrio et al. (2014), Sweden | Cohort study | | | Paternal age 20–24 years | Adjusted for maternal age, sex, year of birth, parental education, history of psychiatric hospitalization | High |
Durkin et al. (2008), USA | Cohort study | 1251 cases with autism 253 347 population
| | Paternal age 25–29 years | Adjusted for maternal age, birth order, gender, maternal education, ethnicity, multiple birth, gestational age, BW for gestational age | High |
Frans et al. (2013), Sweden | Case control | 5936 cases with autism 30 923 controls
| Paternal age: 45–49 years AOR 1.85 (1.47–2.31) ≥50 years AOR 2.23 (1.59–3.12) With each 10 years RR 1.25 (95% CI 1.17, 1.31)
| Paternal age 20–24 years | Adjusted for maternal age, birth year, gender, family history, educational level, country | Medium |
Grether et al. (2009), USA | Cohort study | 23 311 cases with autism 7 550 026 population | Paternal age: 50–54 years AOR 1.53 (1.32–1.77) 60–64 years AOR 2.05 (1.38–3.05) With each 10 year increase in paternal age (15–64 years) ARR 1.22 (1.18, 1.25)
| Paternal age 25–29 years | Adjusted for maternal age, child’s sex, birth weight, ethnicity, education, parity, gestational age, delivery method, birth year | High |
Hultman et al. (2011), Sweden | Cohort study | 883 cases with autism 1 075 588 population | Paternal age: 30–39 years AOR 1.19 (1.00–1.42) 40–49 years AOR 1.42 (1.07–1.87) ≥50 years AOR 2.21 (1.26–3.88) ≥55 years AOR 4.36 (2.09–9.09) With each 10 year increase in paternal age RR 1.21 (1.10, 1.34)
| Paternal age <29 years | Adjusted for maternal age, maternal country of birth, birth weight, maternal history of psychiatric illness, paternal country of birth, paternal history of psychiatric illness, BW, being small/large for gestational age, foetal distress, SES, birth order, year of birth of the offspring | Medium |
Idring et al. (2014), Sweden | Cohort study | 4746 cases with ASD 417 303 population
| Paternal age: 25–28 years AOR 0.93 (0.90–0.96) 35–39 years AOR 1.07 (1.04–1.10) 55–59 years AOR 1.39 (1.29–1.50)
| Paternal age 32 years | Adjusted for maternal age (using generalized additive models - GAMs), birth year, sex, parity, parental psychiatric history, occupational class, family income, maternal region of birth | High |
King et al. (2009), USA | Cohort study | 18 731 cases with autism 4 906 926 population
| | Paternal age <30 years | | Medium |
Lampi et al. (2013), Finland | Case control | 4713 cases with ASD 1132 with childhood autism 1785 with Asperger’s syndrome 1796 with pervasive development disorder (PDD) 18 777 controls
| Paternal age: Autism: 40–49 years AOR 1.6 (1.1–2.3) Asperger: 40–49 years AOR 1.1 (0.5–2.2) PDD: 40–49 years AOR 1.6 (0.8–3.2)
| Paternal age 25–29 years | Adjusted for maternal age, number of previous births, weight for gestational age, intellectual disability, maternal SES, paternal psychiatric history. | Medium |
Larsson et al. (2005), Denmark | Case control | 698 cases with autism 17 450 controls
| | Paternal age 25–29 years | Adjusted for perinatal factors, maternal age, parental psychiatric history, socio-economic characteristics | Medium |
Lauritsen et al. (2005) Denmark | Cohort study | 818 cases with autism 943 664 population
| | Paternal age 25–29 years | Adjusted for maternal age, gender, calendar year of diagnosis, paternal history of psychiatric disease, parental country of birth | Medium |
Lundstrom et al. (2010), Sweden | Cohort (twin cohort) - Sweden and UK | Sweden: 164 cases with ASD 11 122 population UK: 66 cases with ASD 13 524 population
| Paternal age in Sweden: 45–50 years AOR 1.90 (1.73–4.92) ≥51 years AOR 3.37 (1.02–11.14) Paternal age in UK: 45–49 years AOR 1.66 (0.47–5.82) ≥51 years AOR 3.59 (0.37–34.46)
| Paternal age 25–34 years | | Medium |
Maimburg and Vaeth (2006), Denmark | Case control | | | Paternal age 25–29 years | Adjusted for maternal age, maternal citizenship, BW, gestational age, Apgar score, birth defect, irregular foetal position | Medium |
Mamidala et al. (2013), India | Case control | 471 cases with ASD471 controls | | Paternal age <30 years | Adjusted for maternal age, gender, year of birth | Medium |
Parner et al. (2012), Denmark | Cohort study (sibling design) | 9556 cases with ASD 1 311 736 children
| | Paternal age <35 years | Combinations of parents’ ages: for mothers younger than 35 years, the risk of ASD increased with increasing father’s age group. Adjusted for gestational age, birth weight, birth order, sex, parental psychiatric history at birth | Medium |
Quinlan et al. (2015), USA (New York) | Cohort study | 1589 cases with ASD 927 003 population
| | Paternal age <25 years | Adjusted for parity, sex, race and ethnicity, gestational age, maternal metabolic risk factor, SGA. Not precise whether adjusted for maternal age | Medium |
Reichenberg et al. (2006), Israel | Cohort study | 319 cases with ASD 132 271 population
| | Paternal age 15–29 years | Adjusted for year of birth, SES and maternal age | Medium |
Sandin et al. (2016), Scandinavia (Danmark, Norge, Sweden), Western Australia and Israel | Cohort study | 30 902 cases with ASD 5 776 794 population
| Paternal age and risk for ASD: <20 years ARR 1.08 (0.92–1.27) 30–39 years ARR 1.05 (1.02–1.08) 40–49 years ARR 1.28 (1.22–1.34) ≥50 years ARR 1.64 (1.66–1.85)
| Paternal age 20–29 years | Joint effect of maternal and paternal age with increasing risk for couples with increasing differences in parental age. Adjusted for site (country), sex, birth year, maternal age
| High |
Sasanfar et al. (2010), Iran | Case control study | 179 cases with ASD 1611 controls
| | Cohort study: Paternal age 25–29 years Case control study: Paternal age 25–29 years
| Adjusted for parental education, birth order, sex, consanguinity, urbanism and province. Not precise whether adjusted for maternal age | Low |
Shelton et al. (2010), USA | Cohort study | 4 947 935 population 12 159 cases with autism
| | Paternal age 25–29 years | Adjusted for maternal age, parents race/ethnicity, year of birth, insurance type, parental education | Medium |
Tsuchiya et al. (2008), Japan | Case control | | Paternal age: 29–32 years: AOR 2.28 (1.02–5.11) ≥33 years: AOR 3.09 (1.17–8.16) Paternal age as a continuous variable: AOR 2.54 (0.96–6.72)
| Paternal age <29 years | | Low |
van Balkom et al. (2012), Aruba, The Netherlands | Case control | 95 cases with ASD 347 controls
| | Paternal age <30 years | Adjusted for maternal age and PTB | Low |
Zhang et al. (2010), China | Case control | 95 cases with autism 95 controls
| | Paternal age <30 years | Adjusted for paternal age, gender and birth year. No adjustments for maternal age | Low |
Table IVStudies on the association of paternal age with autism/ASDs in offspring.
Author, year, country
. | Study design
. | Number of children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Adjustments
. |
---|
Outcome
. | Reference group/control
. |
---|
Systematic review and meta-analysis n = 2 |
Hultman et al. (2011), Sweden | | 11 studies (including 12 cohorts) with paternal age as exposure | Pooled estimates: 30–39 years 1.22 (1.05–1.42) 40–49 years 1.78 (1.52–2.07) ≥50 years 2.46 (2.20–2.76)
| Paternal age ≤29 years | Increased risk of autism with increased paternal age | Medium |
Wu et al. (2017), China | Systematic review and meta-analysis | 27 studies (6 cohort and 21 case control studies) with paternal age as exposure | | Reference point: Midpoint paternal age -age not mentioned
| Compared to reference point, lower paternal age was associated with reduced risk and increased paternal age was associated with increased risk of autism | Medium |
Original articles n = 28 |
Ben Itzchak et al. (2011), Israel | Cohort study | | Paternal age in a cohort with ASD. No risk estimate. | Paternal age 20–29 years | The percentage of fathers in the older age (30–40 years) was significantly higher in the ASD cohort compared to the Israeli newborn data (P < 0,01) | Low |
Bilder et al. (2009), USA | Case control | 132 cases with ASD 13 200 controls
| Paternal age: OR 1.28 (0.54–3.03)
| Paternal age 30–39 years | | Low |
Buizer-Voskamp et al. (2011), The Netherlands | Case control | | | Paternal age 25–29 years | Adjusted for maternal age <30 years and >30 years, ethnic background and average income of the residential area | Medium |
Burd et al. (1999a), USA | Case control study | 78 cases of autism 390 controls
| | Paternal age <20 or >30, 20–30 years
| | Low |
Byars and Boomsma (2016), Denmark | Cohort study | | Paternal age: 26–30 years AHR 0.92 (0.86–0.98) 35–39 years AHR 1.10 (1.03–1.18) 40–44 years AHR 1.19 (1.06–1.33) 45–60 years AHR 1.2 (1.04–1.49)
| Paternal age 31–34 years | Adjusted for other parent’s age (see STable I) | Medium |
Croen et al. (2007), USA | Case control | 593 cases with autism 132 251 population
| Paternal age: 35–39 years AOR 1.38 (1.04–1.84) ≥40 years AOR 1.52 (1.10–2.10) With each 10 year increase in paternal age ARR 1.34 (1.06–1.69)
| Paternal age 25–29 years | Adjusted for maternal age, birth order, gender, date of birth, parental educational level, ethnicity | Medium |
D’Onofrio et al. (2014), Sweden | Cohort study | | | Paternal age 20–24 years | Adjusted for maternal age, sex, year of birth, parental education, history of psychiatric hospitalization | High |
Durkin et al. (2008), USA | Cohort study | 1251 cases with autism 253 347 population
| | Paternal age 25–29 years | Adjusted for maternal age, birth order, gender, maternal education, ethnicity, multiple birth, gestational age, BW for gestational age | High |
Frans et al. (2013), Sweden | Case control | 5936 cases with autism 30 923 controls
| Paternal age: 45–49 years AOR 1.85 (1.47–2.31) ≥50 years AOR 2.23 (1.59–3.12) With each 10 years RR 1.25 (95% CI 1.17, 1.31)
| Paternal age 20–24 years | Adjusted for maternal age, birth year, gender, family history, educational level, country | Medium |
Grether et al. (2009), USA | Cohort study | 23 311 cases with autism 7 550 026 population | Paternal age: 50–54 years AOR 1.53 (1.32–1.77) 60–64 years AOR 2.05 (1.38–3.05) With each 10 year increase in paternal age (15–64 years) ARR 1.22 (1.18, 1.25)
| Paternal age 25–29 years | Adjusted for maternal age, child’s sex, birth weight, ethnicity, education, parity, gestational age, delivery method, birth year | High |
Hultman et al. (2011), Sweden | Cohort study | 883 cases with autism 1 075 588 population | Paternal age: 30–39 years AOR 1.19 (1.00–1.42) 40–49 years AOR 1.42 (1.07–1.87) ≥50 years AOR 2.21 (1.26–3.88) ≥55 years AOR 4.36 (2.09–9.09) With each 10 year increase in paternal age RR 1.21 (1.10, 1.34)
| Paternal age <29 years | Adjusted for maternal age, maternal country of birth, birth weight, maternal history of psychiatric illness, paternal country of birth, paternal history of psychiatric illness, BW, being small/large for gestational age, foetal distress, SES, birth order, year of birth of the offspring | Medium |
Idring et al. (2014), Sweden | Cohort study | 4746 cases with ASD 417 303 population
| Paternal age: 25–28 years AOR 0.93 (0.90–0.96) 35–39 years AOR 1.07 (1.04–1.10) 55–59 years AOR 1.39 (1.29–1.50)
| Paternal age 32 years | Adjusted for maternal age (using generalized additive models - GAMs), birth year, sex, parity, parental psychiatric history, occupational class, family income, maternal region of birth | High |
King et al. (2009), USA | Cohort study | 18 731 cases with autism 4 906 926 population
| | Paternal age <30 years | | Medium |
Lampi et al. (2013), Finland | Case control | 4713 cases with ASD 1132 with childhood autism 1785 with Asperger’s syndrome 1796 with pervasive development disorder (PDD) 18 777 controls
| Paternal age: Autism: 40–49 years AOR 1.6 (1.1–2.3) Asperger: 40–49 years AOR 1.1 (0.5–2.2) PDD: 40–49 years AOR 1.6 (0.8–3.2)
| Paternal age 25–29 years | Adjusted for maternal age, number of previous births, weight for gestational age, intellectual disability, maternal SES, paternal psychiatric history. | Medium |
Larsson et al. (2005), Denmark | Case control | 698 cases with autism 17 450 controls
| | Paternal age 25–29 years | Adjusted for perinatal factors, maternal age, parental psychiatric history, socio-economic characteristics | Medium |
Lauritsen et al. (2005) Denmark | Cohort study | 818 cases with autism 943 664 population
| | Paternal age 25–29 years | Adjusted for maternal age, gender, calendar year of diagnosis, paternal history of psychiatric disease, parental country of birth | Medium |
Lundstrom et al. (2010), Sweden | Cohort (twin cohort) - Sweden and UK | Sweden: 164 cases with ASD 11 122 population UK: 66 cases with ASD 13 524 population
| Paternal age in Sweden: 45–50 years AOR 1.90 (1.73–4.92) ≥51 years AOR 3.37 (1.02–11.14) Paternal age in UK: 45–49 years AOR 1.66 (0.47–5.82) ≥51 years AOR 3.59 (0.37–34.46)
| Paternal age 25–34 years | | Medium |
Maimburg and Vaeth (2006), Denmark | Case control | | | Paternal age 25–29 years | Adjusted for maternal age, maternal citizenship, BW, gestational age, Apgar score, birth defect, irregular foetal position | Medium |
Mamidala et al. (2013), India | Case control | 471 cases with ASD471 controls | | Paternal age <30 years | Adjusted for maternal age, gender, year of birth | Medium |
Parner et al. (2012), Denmark | Cohort study (sibling design) | 9556 cases with ASD 1 311 736 children
| | Paternal age <35 years | Combinations of parents’ ages: for mothers younger than 35 years, the risk of ASD increased with increasing father’s age group. Adjusted for gestational age, birth weight, birth order, sex, parental psychiatric history at birth | Medium |
Quinlan et al. (2015), USA (New York) | Cohort study | 1589 cases with ASD 927 003 population
| | Paternal age <25 years | Adjusted for parity, sex, race and ethnicity, gestational age, maternal metabolic risk factor, SGA. Not precise whether adjusted for maternal age | Medium |
Reichenberg et al. (2006), Israel | Cohort study | 319 cases with ASD 132 271 population
| | Paternal age 15–29 years | Adjusted for year of birth, SES and maternal age | Medium |
Sandin et al. (2016), Scandinavia (Danmark, Norge, Sweden), Western Australia and Israel | Cohort study | 30 902 cases with ASD 5 776 794 population
| Paternal age and risk for ASD: <20 years ARR 1.08 (0.92–1.27) 30–39 years ARR 1.05 (1.02–1.08) 40–49 years ARR 1.28 (1.22–1.34) ≥50 years ARR 1.64 (1.66–1.85)
| Paternal age 20–29 years | Joint effect of maternal and paternal age with increasing risk for couples with increasing differences in parental age. Adjusted for site (country), sex, birth year, maternal age
| High |
Sasanfar et al. (2010), Iran | Case control study | 179 cases with ASD 1611 controls
| | Cohort study: Paternal age 25–29 years Case control study: Paternal age 25–29 years
| Adjusted for parental education, birth order, sex, consanguinity, urbanism and province. Not precise whether adjusted for maternal age | Low |
Shelton et al. (2010), USA | Cohort study | 4 947 935 population 12 159 cases with autism
| | Paternal age 25–29 years | Adjusted for maternal age, parents race/ethnicity, year of birth, insurance type, parental education | Medium |
Tsuchiya et al. (2008), Japan | Case control | | Paternal age: 29–32 years: AOR 2.28 (1.02–5.11) ≥33 years: AOR 3.09 (1.17–8.16) Paternal age as a continuous variable: AOR 2.54 (0.96–6.72)
| Paternal age <29 years | | Low |
van Balkom et al. (2012), Aruba, The Netherlands | Case control | 95 cases with ASD 347 controls
| | Paternal age <30 years | Adjusted for maternal age and PTB | Low |
Zhang et al. (2010), China | Case control | 95 cases with autism 95 controls
| | Paternal age <30 years | Adjusted for paternal age, gender and birth year. No adjustments for maternal age | Low |
Author, year, country
. | Study design
. | Number of children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Adjustments
. |
---|
Outcome
. | Reference group/control
. |
---|
Systematic review and meta-analysis n = 2 |
Hultman et al. (2011), Sweden | | 11 studies (including 12 cohorts) with paternal age as exposure | Pooled estimates: 30–39 years 1.22 (1.05–1.42) 40–49 years 1.78 (1.52–2.07) ≥50 years 2.46 (2.20–2.76)
| Paternal age ≤29 years | Increased risk of autism with increased paternal age | Medium |
Wu et al. (2017), China | Systematic review and meta-analysis | 27 studies (6 cohort and 21 case control studies) with paternal age as exposure | | Reference point: Midpoint paternal age -age not mentioned
| Compared to reference point, lower paternal age was associated with reduced risk and increased paternal age was associated with increased risk of autism | Medium |
Original articles n = 28 |
Ben Itzchak et al. (2011), Israel | Cohort study | | Paternal age in a cohort with ASD. No risk estimate. | Paternal age 20–29 years | The percentage of fathers in the older age (30–40 years) was significantly higher in the ASD cohort compared to the Israeli newborn data (P < 0,01) | Low |
Bilder et al. (2009), USA | Case control | 132 cases with ASD 13 200 controls
| Paternal age: OR 1.28 (0.54–3.03)
| Paternal age 30–39 years | | Low |
Buizer-Voskamp et al. (2011), The Netherlands | Case control | | | Paternal age 25–29 years | Adjusted for maternal age <30 years and >30 years, ethnic background and average income of the residential area | Medium |
Burd et al. (1999a), USA | Case control study | 78 cases of autism 390 controls
| | Paternal age <20 or >30, 20–30 years
| | Low |
Byars and Boomsma (2016), Denmark | Cohort study | | Paternal age: 26–30 years AHR 0.92 (0.86–0.98) 35–39 years AHR 1.10 (1.03–1.18) 40–44 years AHR 1.19 (1.06–1.33) 45–60 years AHR 1.2 (1.04–1.49)
| Paternal age 31–34 years | Adjusted for other parent’s age (see STable I) | Medium |
Croen et al. (2007), USA | Case control | 593 cases with autism 132 251 population
| Paternal age: 35–39 years AOR 1.38 (1.04–1.84) ≥40 years AOR 1.52 (1.10–2.10) With each 10 year increase in paternal age ARR 1.34 (1.06–1.69)
| Paternal age 25–29 years | Adjusted for maternal age, birth order, gender, date of birth, parental educational level, ethnicity | Medium |
D’Onofrio et al. (2014), Sweden | Cohort study | | | Paternal age 20–24 years | Adjusted for maternal age, sex, year of birth, parental education, history of psychiatric hospitalization | High |
Durkin et al. (2008), USA | Cohort study | 1251 cases with autism 253 347 population
| | Paternal age 25–29 years | Adjusted for maternal age, birth order, gender, maternal education, ethnicity, multiple birth, gestational age, BW for gestational age | High |
Frans et al. (2013), Sweden | Case control | 5936 cases with autism 30 923 controls
| Paternal age: 45–49 years AOR 1.85 (1.47–2.31) ≥50 years AOR 2.23 (1.59–3.12) With each 10 years RR 1.25 (95% CI 1.17, 1.31)
| Paternal age 20–24 years | Adjusted for maternal age, birth year, gender, family history, educational level, country | Medium |
Grether et al. (2009), USA | Cohort study | 23 311 cases with autism 7 550 026 population | Paternal age: 50–54 years AOR 1.53 (1.32–1.77) 60–64 years AOR 2.05 (1.38–3.05) With each 10 year increase in paternal age (15–64 years) ARR 1.22 (1.18, 1.25)
| Paternal age 25–29 years | Adjusted for maternal age, child’s sex, birth weight, ethnicity, education, parity, gestational age, delivery method, birth year | High |
Hultman et al. (2011), Sweden | Cohort study | 883 cases with autism 1 075 588 population | Paternal age: 30–39 years AOR 1.19 (1.00–1.42) 40–49 years AOR 1.42 (1.07–1.87) ≥50 years AOR 2.21 (1.26–3.88) ≥55 years AOR 4.36 (2.09–9.09) With each 10 year increase in paternal age RR 1.21 (1.10, 1.34)
| Paternal age <29 years | Adjusted for maternal age, maternal country of birth, birth weight, maternal history of psychiatric illness, paternal country of birth, paternal history of psychiatric illness, BW, being small/large for gestational age, foetal distress, SES, birth order, year of birth of the offspring | Medium |
Idring et al. (2014), Sweden | Cohort study | 4746 cases with ASD 417 303 population
| Paternal age: 25–28 years AOR 0.93 (0.90–0.96) 35–39 years AOR 1.07 (1.04–1.10) 55–59 years AOR 1.39 (1.29–1.50)
| Paternal age 32 years | Adjusted for maternal age (using generalized additive models - GAMs), birth year, sex, parity, parental psychiatric history, occupational class, family income, maternal region of birth | High |
King et al. (2009), USA | Cohort study | 18 731 cases with autism 4 906 926 population
| | Paternal age <30 years | | Medium |
Lampi et al. (2013), Finland | Case control | 4713 cases with ASD 1132 with childhood autism 1785 with Asperger’s syndrome 1796 with pervasive development disorder (PDD) 18 777 controls
| Paternal age: Autism: 40–49 years AOR 1.6 (1.1–2.3) Asperger: 40–49 years AOR 1.1 (0.5–2.2) PDD: 40–49 years AOR 1.6 (0.8–3.2)
| Paternal age 25–29 years | Adjusted for maternal age, number of previous births, weight for gestational age, intellectual disability, maternal SES, paternal psychiatric history. | Medium |
Larsson et al. (2005), Denmark | Case control | 698 cases with autism 17 450 controls
| | Paternal age 25–29 years | Adjusted for perinatal factors, maternal age, parental psychiatric history, socio-economic characteristics | Medium |
Lauritsen et al. (2005) Denmark | Cohort study | 818 cases with autism 943 664 population
| | Paternal age 25–29 years | Adjusted for maternal age, gender, calendar year of diagnosis, paternal history of psychiatric disease, parental country of birth | Medium |
Lundstrom et al. (2010), Sweden | Cohort (twin cohort) - Sweden and UK | Sweden: 164 cases with ASD 11 122 population UK: 66 cases with ASD 13 524 population
| Paternal age in Sweden: 45–50 years AOR 1.90 (1.73–4.92) ≥51 years AOR 3.37 (1.02–11.14) Paternal age in UK: 45–49 years AOR 1.66 (0.47–5.82) ≥51 years AOR 3.59 (0.37–34.46)
| Paternal age 25–34 years | | Medium |
Maimburg and Vaeth (2006), Denmark | Case control | | | Paternal age 25–29 years | Adjusted for maternal age, maternal citizenship, BW, gestational age, Apgar score, birth defect, irregular foetal position | Medium |
Mamidala et al. (2013), India | Case control | 471 cases with ASD471 controls | | Paternal age <30 years | Adjusted for maternal age, gender, year of birth | Medium |
Parner et al. (2012), Denmark | Cohort study (sibling design) | 9556 cases with ASD 1 311 736 children
| | Paternal age <35 years | Combinations of parents’ ages: for mothers younger than 35 years, the risk of ASD increased with increasing father’s age group. Adjusted for gestational age, birth weight, birth order, sex, parental psychiatric history at birth | Medium |
Quinlan et al. (2015), USA (New York) | Cohort study | 1589 cases with ASD 927 003 population
| | Paternal age <25 years | Adjusted for parity, sex, race and ethnicity, gestational age, maternal metabolic risk factor, SGA. Not precise whether adjusted for maternal age | Medium |
Reichenberg et al. (2006), Israel | Cohort study | 319 cases with ASD 132 271 population
| | Paternal age 15–29 years | Adjusted for year of birth, SES and maternal age | Medium |
Sandin et al. (2016), Scandinavia (Danmark, Norge, Sweden), Western Australia and Israel | Cohort study | 30 902 cases with ASD 5 776 794 population
| Paternal age and risk for ASD: <20 years ARR 1.08 (0.92–1.27) 30–39 years ARR 1.05 (1.02–1.08) 40–49 years ARR 1.28 (1.22–1.34) ≥50 years ARR 1.64 (1.66–1.85)
| Paternal age 20–29 years | Joint effect of maternal and paternal age with increasing risk for couples with increasing differences in parental age. Adjusted for site (country), sex, birth year, maternal age
| High |
Sasanfar et al. (2010), Iran | Case control study | 179 cases with ASD 1611 controls
| | Cohort study: Paternal age 25–29 years Case control study: Paternal age 25–29 years
| Adjusted for parental education, birth order, sex, consanguinity, urbanism and province. Not precise whether adjusted for maternal age | Low |
Shelton et al. (2010), USA | Cohort study | 4 947 935 population 12 159 cases with autism
| | Paternal age 25–29 years | Adjusted for maternal age, parents race/ethnicity, year of birth, insurance type, parental education | Medium |
Tsuchiya et al. (2008), Japan | Case control | | Paternal age: 29–32 years: AOR 2.28 (1.02–5.11) ≥33 years: AOR 3.09 (1.17–8.16) Paternal age as a continuous variable: AOR 2.54 (0.96–6.72)
| Paternal age <29 years | | Low |
van Balkom et al. (2012), Aruba, The Netherlands | Case control | 95 cases with ASD 347 controls
| | Paternal age <30 years | Adjusted for maternal age and PTB | Low |
Zhang et al. (2010), China | Case control | 95 cases with autism 95 controls
| | Paternal age <30 years | Adjusted for paternal age, gender and birth year. No adjustments for maternal age | Low |
Figure 12
Forest plot describing the association between paternal age and risk for autism/ASDs in the offspring.
Conclusion: Higher paternal age is probably associated with an increase in autism/ASD. Moderate certainty of evidence (GRADE⊕⊕⊕○)
Schizophrenia
Three meta-analyses (Wohl and Gorwood, 2007; Torrey et al., 2009; Miller et al., 2010) and 19 original studies assessed the effect of paternal age on the risk of schizophrenia in offspring. The original articles included 10 cohort studies and 9 case control studies. No studies of high quality, 9 of medium quality and 10 of low quality were included (Supplementary Table SI, Table V). The meta-analysis by Miller et al. (2010) included six cohort and six case control studies. In both study designs, a significant increase in the risk of schizophrenia in the offspring of older fathers was found. The relative risk in the oldest fathers (≥50 years) was 1.66 (95% CI 1.46–1.89). The meta-analysis by Torrey et al. (2009) included ten studies and found an increased risk of schizophrenia in the offspring of the older fathers. The pooled estimate of risk of schizophrenia in offspring of fathers ≥55 years of age was 2.21 (95% CI 1.46–3.37) and for fathers ≥45 years the pooled estimate was 1.38 (95% CI 0.95–2.01). Wohl and Gorwood (2007) reported an association with paternal age, with higher levels of schizophrenia in the offspring of fathers younger than 20 and older than 35 years.
Table VStudies on the association of paternal age with schizophrenia and schizophrenia spectrum disorders in offspring.
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Adjustments
. |
---|
Outcomes (Risk estimates)
. | Reference group/ Control
. |
---|
Systematic reviews n = 3 |
Miller et al. (2011), Finland | SR (6 cohort and 6 case control studies) and MA | | | Paternal age 25–29 years | | Medium |
Torrey et al. (2009), USA | MA (10 studies) | 10 studies included | | NA | Matched for city of birth, season of birth and parental history of treatment for mental disorder | Low |
Wohl and Gorwood (2007), France | MA (8 studies) | 8 out of 10 studies were included | | Paternal age 25–34 years | | Low |
Original articles n = 19 |
Brown et al. (2002), USA | Cohort study | 12 094 individuals | 73% response rate (146 of 170) Risk for each 10-year increase in paternal age: ARR 1.89 (1.08–3.32), Z = 2.22, P < 0.03
| Paternal age 15–24 years | Adjusted for maternal age Small study size (71 cases) Includes both schizophrenia and other schizophrenia spectrum diseases (SSD)
| Low |
Buizer-Voskamp et al. (2011), The Netherlands | Case control | 14 231 cases 56 925 controls
| | Paternal age 25–29 years | Adjusted for maternal age, SES, and ethnic background Separate analyses for male and female offspring
| Medium |
Byars and Boomsma (2016), Denmark | Cohort study | 1 787 447 children | 7 out of 15 risk ratios increased in the three age-difference groups Estimates not given | NA | | Low |
Byrne et al. (2003), USA | Case control | 7704 cases 192 590 controls
| | Paternal age 20–24 years | Adjusted for maternal age, parental education, wealth, marital status and family history of psychiatric history | Medium |
Dalman and Allebeck (2002), Sweden | Case control | | | Paternal age 20–24 years | | Low |
Ek et al. (2015), Sweden | Cohort study | 3829 cases 2 589 502 individuals
| Paternal age >45 years: HR 0.93 (0.72–1.21) 35–39 years: HR 1.37 (1.18–1.58) 40–44 years: HR 1.81 (1.44–2.28)
| Paternal age 25–29 years | | Low |
Frans et al. (2011), Sweden | Cohort study | 120 758 individuals | | Paternal age 20–24 years | Adjusted for maternal age, birth year | Medium |
Lehrer et al. (2016), USA | Case control | | | Paternal age 20–24 years | | Medium |
Malaspina et al. (2001), Israel | Cohort | | Paternal age 40–44 years: ARR 1.79 (1.25–2.57) 45–49 years: ARR 1.89 (1.24–2.88) >50 years: ARR 2.60 (1.63–4.15)
| Paternal age 20–24 years | Adjusted for maternal age, sex and ethnic group | Low |
McGrath et al. (2014), Denmark | Cohort | 2 894 688 people | | Paternal age 25–29 years | The cohort was observed for 42.7 million person-years | Medium |
Naserbakht et al. (2011), Iran | Case control | | Birth rank comparisons: 35% versus 24% of the cases versus the controls were in the third or upper birth rank (P = 0.01). Mean age of fathers at birth in cases (30 ± 6.26 years) versus controls (26.45 ± 5.64 years; P = 0.0001). Paternal age ≥32 years (at birth) in cases versus controls: AOR 3.8 (1.80 to 4.27) | NA | | Low |
Petersen et al. (2011), Denmark | Cohort | 2.2 million people | Paternal age: 45–49 years: AIRR 1.39 (1.13–1.70) 50–54 years: AIRR 1.93 (1.49–2.50) >55 years: AIRR 1.15 (1.12-1-20)
| Paternal age 25–29 years | Adjusted for maternal age, proband sex, family psychiatric history in father, mother and siblings The risk of schizophrenia increased with increased paternal age of the father´s first child
| Medium |
Sipos et al. (2004), Sweden | Cohort | 754 330 people | | Paternal age 21–24 years | Separate analysis according to family history of the disorder. Adjusted for maternal age, BW, GA, parity and plurality
| Low |
Sorensen et al. (2014), Denmark | Cohort | 176 454 men | | Paternal age 25–29 years | | Medium |
Torrey et al. (2009), USA | Cohort + MA (10 studies) | 168 + 88 cases 25 025 controls
| Cohort of 88 cases: Paternal age: >35 years: OR 1.35 (0.88–2.06) >40 years: OR 1.33 (0.75–2.37) >45 years: OR 1.32 (0.48–3.63) ≥55 years: MA: pooled OR 2.21 (1.46–3.37)
| NA | Matched for city of birth, season of birth and parental history of treatment for mental disorder | Low |
Tsuchiya et al. (2005), Japan | Case control | 99 cases, 381 controls | | Paternal age < 25 years | Adjusted for age and gender of the subject, parity, family history and maternal age. | Low |
Wang et al. (2015), Taiwan | Case series | 1297 cases | | Paternal age 21–24 years | Study of earlier onset among co-affected sib-pairs with the same familial predisposition. Adjusted for maternal age, gender, education in years and parental education
| Low |
Wu et al. (2012), China | Case control | | 351 patients with schizophrenia (167 males, 134 females) Paternal age: <25 years: OR 0.628 (0.350–1.127) 30–34 years: OR 2.660 (1.697–4.169) >35 years: OR 10.183 (4.772–21.729)
| Paternal age 25–29 years | Adjusted for participant´s sex, age and maternal age | Low |
Zammit et al. (2003), Sweden | Cohort | 2362 cases 50 087 individuals
| | Paternal age 15–24 years | Adjusted for maternal age, drug use, poor social integration and place of upbringing. | |
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Adjustments
. |
---|
Outcomes (Risk estimates)
. | Reference group/ Control
. |
---|
Systematic reviews n = 3 |
Miller et al. (2011), Finland | SR (6 cohort and 6 case control studies) and MA | | | Paternal age 25–29 years | | Medium |
Torrey et al. (2009), USA | MA (10 studies) | 10 studies included | | NA | Matched for city of birth, season of birth and parental history of treatment for mental disorder | Low |
Wohl and Gorwood (2007), France | MA (8 studies) | 8 out of 10 studies were included | | Paternal age 25–34 years | | Low |
Original articles n = 19 |
Brown et al. (2002), USA | Cohort study | 12 094 individuals | 73% response rate (146 of 170) Risk for each 10-year increase in paternal age: ARR 1.89 (1.08–3.32), Z = 2.22, P < 0.03
| Paternal age 15–24 years | Adjusted for maternal age Small study size (71 cases) Includes both schizophrenia and other schizophrenia spectrum diseases (SSD)
| Low |
Buizer-Voskamp et al. (2011), The Netherlands | Case control | 14 231 cases 56 925 controls
| | Paternal age 25–29 years | Adjusted for maternal age, SES, and ethnic background Separate analyses for male and female offspring
| Medium |
Byars and Boomsma (2016), Denmark | Cohort study | 1 787 447 children | 7 out of 15 risk ratios increased in the three age-difference groups Estimates not given | NA | | Low |
Byrne et al. (2003), USA | Case control | 7704 cases 192 590 controls
| | Paternal age 20–24 years | Adjusted for maternal age, parental education, wealth, marital status and family history of psychiatric history | Medium |
Dalman and Allebeck (2002), Sweden | Case control | | | Paternal age 20–24 years | | Low |
Ek et al. (2015), Sweden | Cohort study | 3829 cases 2 589 502 individuals
| Paternal age >45 years: HR 0.93 (0.72–1.21) 35–39 years: HR 1.37 (1.18–1.58) 40–44 years: HR 1.81 (1.44–2.28)
| Paternal age 25–29 years | | Low |
Frans et al. (2011), Sweden | Cohort study | 120 758 individuals | | Paternal age 20–24 years | Adjusted for maternal age, birth year | Medium |
Lehrer et al. (2016), USA | Case control | | | Paternal age 20–24 years | | Medium |
Malaspina et al. (2001), Israel | Cohort | | Paternal age 40–44 years: ARR 1.79 (1.25–2.57) 45–49 years: ARR 1.89 (1.24–2.88) >50 years: ARR 2.60 (1.63–4.15)
| Paternal age 20–24 years | Adjusted for maternal age, sex and ethnic group | Low |
McGrath et al. (2014), Denmark | Cohort | 2 894 688 people | | Paternal age 25–29 years | The cohort was observed for 42.7 million person-years | Medium |
Naserbakht et al. (2011), Iran | Case control | | Birth rank comparisons: 35% versus 24% of the cases versus the controls were in the third or upper birth rank (P = 0.01). Mean age of fathers at birth in cases (30 ± 6.26 years) versus controls (26.45 ± 5.64 years; P = 0.0001). Paternal age ≥32 years (at birth) in cases versus controls: AOR 3.8 (1.80 to 4.27) | NA | | Low |
Petersen et al. (2011), Denmark | Cohort | 2.2 million people | Paternal age: 45–49 years: AIRR 1.39 (1.13–1.70) 50–54 years: AIRR 1.93 (1.49–2.50) >55 years: AIRR 1.15 (1.12-1-20)
| Paternal age 25–29 years | Adjusted for maternal age, proband sex, family psychiatric history in father, mother and siblings The risk of schizophrenia increased with increased paternal age of the father´s first child
| Medium |
Sipos et al. (2004), Sweden | Cohort | 754 330 people | | Paternal age 21–24 years | Separate analysis according to family history of the disorder. Adjusted for maternal age, BW, GA, parity and plurality
| Low |
Sorensen et al. (2014), Denmark | Cohort | 176 454 men | | Paternal age 25–29 years | | Medium |
Torrey et al. (2009), USA | Cohort + MA (10 studies) | 168 + 88 cases 25 025 controls
| Cohort of 88 cases: Paternal age: >35 years: OR 1.35 (0.88–2.06) >40 years: OR 1.33 (0.75–2.37) >45 years: OR 1.32 (0.48–3.63) ≥55 years: MA: pooled OR 2.21 (1.46–3.37)
| NA | Matched for city of birth, season of birth and parental history of treatment for mental disorder | Low |
Tsuchiya et al. (2005), Japan | Case control | 99 cases, 381 controls | | Paternal age < 25 years | Adjusted for age and gender of the subject, parity, family history and maternal age. | Low |
Wang et al. (2015), Taiwan | Case series | 1297 cases | | Paternal age 21–24 years | Study of earlier onset among co-affected sib-pairs with the same familial predisposition. Adjusted for maternal age, gender, education in years and parental education
| Low |
Wu et al. (2012), China | Case control | | 351 patients with schizophrenia (167 males, 134 females) Paternal age: <25 years: OR 0.628 (0.350–1.127) 30–34 years: OR 2.660 (1.697–4.169) >35 years: OR 10.183 (4.772–21.729)
| Paternal age 25–29 years | Adjusted for participant´s sex, age and maternal age | Low |
Zammit et al. (2003), Sweden | Cohort | 2362 cases 50 087 individuals
| | Paternal age 15–24 years | Adjusted for maternal age, drug use, poor social integration and place of upbringing. | |
Table VStudies on the association of paternal age with schizophrenia and schizophrenia spectrum disorders in offspring.
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Adjustments
. |
---|
Outcomes (Risk estimates)
. | Reference group/ Control
. |
---|
Systematic reviews n = 3 |
Miller et al. (2011), Finland | SR (6 cohort and 6 case control studies) and MA | | | Paternal age 25–29 years | | Medium |
Torrey et al. (2009), USA | MA (10 studies) | 10 studies included | | NA | Matched for city of birth, season of birth and parental history of treatment for mental disorder | Low |
Wohl and Gorwood (2007), France | MA (8 studies) | 8 out of 10 studies were included | | Paternal age 25–34 years | | Low |
Original articles n = 19 |
Brown et al. (2002), USA | Cohort study | 12 094 individuals | 73% response rate (146 of 170) Risk for each 10-year increase in paternal age: ARR 1.89 (1.08–3.32), Z = 2.22, P < 0.03
| Paternal age 15–24 years | Adjusted for maternal age Small study size (71 cases) Includes both schizophrenia and other schizophrenia spectrum diseases (SSD)
| Low |
Buizer-Voskamp et al. (2011), The Netherlands | Case control | 14 231 cases 56 925 controls
| | Paternal age 25–29 years | Adjusted for maternal age, SES, and ethnic background Separate analyses for male and female offspring
| Medium |
Byars and Boomsma (2016), Denmark | Cohort study | 1 787 447 children | 7 out of 15 risk ratios increased in the three age-difference groups Estimates not given | NA | | Low |
Byrne et al. (2003), USA | Case control | 7704 cases 192 590 controls
| | Paternal age 20–24 years | Adjusted for maternal age, parental education, wealth, marital status and family history of psychiatric history | Medium |
Dalman and Allebeck (2002), Sweden | Case control | | | Paternal age 20–24 years | | Low |
Ek et al. (2015), Sweden | Cohort study | 3829 cases 2 589 502 individuals
| Paternal age >45 years: HR 0.93 (0.72–1.21) 35–39 years: HR 1.37 (1.18–1.58) 40–44 years: HR 1.81 (1.44–2.28)
| Paternal age 25–29 years | | Low |
Frans et al. (2011), Sweden | Cohort study | 120 758 individuals | | Paternal age 20–24 years | Adjusted for maternal age, birth year | Medium |
Lehrer et al. (2016), USA | Case control | | | Paternal age 20–24 years | | Medium |
Malaspina et al. (2001), Israel | Cohort | | Paternal age 40–44 years: ARR 1.79 (1.25–2.57) 45–49 years: ARR 1.89 (1.24–2.88) >50 years: ARR 2.60 (1.63–4.15)
| Paternal age 20–24 years | Adjusted for maternal age, sex and ethnic group | Low |
McGrath et al. (2014), Denmark | Cohort | 2 894 688 people | | Paternal age 25–29 years | The cohort was observed for 42.7 million person-years | Medium |
Naserbakht et al. (2011), Iran | Case control | | Birth rank comparisons: 35% versus 24% of the cases versus the controls were in the third or upper birth rank (P = 0.01). Mean age of fathers at birth in cases (30 ± 6.26 years) versus controls (26.45 ± 5.64 years; P = 0.0001). Paternal age ≥32 years (at birth) in cases versus controls: AOR 3.8 (1.80 to 4.27) | NA | | Low |
Petersen et al. (2011), Denmark | Cohort | 2.2 million people | Paternal age: 45–49 years: AIRR 1.39 (1.13–1.70) 50–54 years: AIRR 1.93 (1.49–2.50) >55 years: AIRR 1.15 (1.12-1-20)
| Paternal age 25–29 years | Adjusted for maternal age, proband sex, family psychiatric history in father, mother and siblings The risk of schizophrenia increased with increased paternal age of the father´s first child
| Medium |
Sipos et al. (2004), Sweden | Cohort | 754 330 people | | Paternal age 21–24 years | Separate analysis according to family history of the disorder. Adjusted for maternal age, BW, GA, parity and plurality
| Low |
Sorensen et al. (2014), Denmark | Cohort | 176 454 men | | Paternal age 25–29 years | | Medium |
Torrey et al. (2009), USA | Cohort + MA (10 studies) | 168 + 88 cases 25 025 controls
| Cohort of 88 cases: Paternal age: >35 years: OR 1.35 (0.88–2.06) >40 years: OR 1.33 (0.75–2.37) >45 years: OR 1.32 (0.48–3.63) ≥55 years: MA: pooled OR 2.21 (1.46–3.37)
| NA | Matched for city of birth, season of birth and parental history of treatment for mental disorder | Low |
Tsuchiya et al. (2005), Japan | Case control | 99 cases, 381 controls | | Paternal age < 25 years | Adjusted for age and gender of the subject, parity, family history and maternal age. | Low |
Wang et al. (2015), Taiwan | Case series | 1297 cases | | Paternal age 21–24 years | Study of earlier onset among co-affected sib-pairs with the same familial predisposition. Adjusted for maternal age, gender, education in years and parental education
| Low |
Wu et al. (2012), China | Case control | | 351 patients with schizophrenia (167 males, 134 females) Paternal age: <25 years: OR 0.628 (0.350–1.127) 30–34 years: OR 2.660 (1.697–4.169) >35 years: OR 10.183 (4.772–21.729)
| Paternal age 25–29 years | Adjusted for participant´s sex, age and maternal age | Low |
Zammit et al. (2003), Sweden | Cohort | 2362 cases 50 087 individuals
| | Paternal age 15–24 years | Adjusted for maternal age, drug use, poor social integration and place of upbringing. | |
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Adjustments
. |
---|
Outcomes (Risk estimates)
. | Reference group/ Control
. |
---|
Systematic reviews n = 3 |
Miller et al. (2011), Finland | SR (6 cohort and 6 case control studies) and MA | | | Paternal age 25–29 years | | Medium |
Torrey et al. (2009), USA | MA (10 studies) | 10 studies included | | NA | Matched for city of birth, season of birth and parental history of treatment for mental disorder | Low |
Wohl and Gorwood (2007), France | MA (8 studies) | 8 out of 10 studies were included | | Paternal age 25–34 years | | Low |
Original articles n = 19 |
Brown et al. (2002), USA | Cohort study | 12 094 individuals | 73% response rate (146 of 170) Risk for each 10-year increase in paternal age: ARR 1.89 (1.08–3.32), Z = 2.22, P < 0.03
| Paternal age 15–24 years | Adjusted for maternal age Small study size (71 cases) Includes both schizophrenia and other schizophrenia spectrum diseases (SSD)
| Low |
Buizer-Voskamp et al. (2011), The Netherlands | Case control | 14 231 cases 56 925 controls
| | Paternal age 25–29 years | Adjusted for maternal age, SES, and ethnic background Separate analyses for male and female offspring
| Medium |
Byars and Boomsma (2016), Denmark | Cohort study | 1 787 447 children | 7 out of 15 risk ratios increased in the three age-difference groups Estimates not given | NA | | Low |
Byrne et al. (2003), USA | Case control | 7704 cases 192 590 controls
| | Paternal age 20–24 years | Adjusted for maternal age, parental education, wealth, marital status and family history of psychiatric history | Medium |
Dalman and Allebeck (2002), Sweden | Case control | | | Paternal age 20–24 years | | Low |
Ek et al. (2015), Sweden | Cohort study | 3829 cases 2 589 502 individuals
| Paternal age >45 years: HR 0.93 (0.72–1.21) 35–39 years: HR 1.37 (1.18–1.58) 40–44 years: HR 1.81 (1.44–2.28)
| Paternal age 25–29 years | | Low |
Frans et al. (2011), Sweden | Cohort study | 120 758 individuals | | Paternal age 20–24 years | Adjusted for maternal age, birth year | Medium |
Lehrer et al. (2016), USA | Case control | | | Paternal age 20–24 years | | Medium |
Malaspina et al. (2001), Israel | Cohort | | Paternal age 40–44 years: ARR 1.79 (1.25–2.57) 45–49 years: ARR 1.89 (1.24–2.88) >50 years: ARR 2.60 (1.63–4.15)
| Paternal age 20–24 years | Adjusted for maternal age, sex and ethnic group | Low |
McGrath et al. (2014), Denmark | Cohort | 2 894 688 people | | Paternal age 25–29 years | The cohort was observed for 42.7 million person-years | Medium |
Naserbakht et al. (2011), Iran | Case control | | Birth rank comparisons: 35% versus 24% of the cases versus the controls were in the third or upper birth rank (P = 0.01). Mean age of fathers at birth in cases (30 ± 6.26 years) versus controls (26.45 ± 5.64 years; P = 0.0001). Paternal age ≥32 years (at birth) in cases versus controls: AOR 3.8 (1.80 to 4.27) | NA | | Low |
Petersen et al. (2011), Denmark | Cohort | 2.2 million people | Paternal age: 45–49 years: AIRR 1.39 (1.13–1.70) 50–54 years: AIRR 1.93 (1.49–2.50) >55 years: AIRR 1.15 (1.12-1-20)
| Paternal age 25–29 years | Adjusted for maternal age, proband sex, family psychiatric history in father, mother and siblings The risk of schizophrenia increased with increased paternal age of the father´s first child
| Medium |
Sipos et al. (2004), Sweden | Cohort | 754 330 people | | Paternal age 21–24 years | Separate analysis according to family history of the disorder. Adjusted for maternal age, BW, GA, parity and plurality
| Low |
Sorensen et al. (2014), Denmark | Cohort | 176 454 men | | Paternal age 25–29 years | | Medium |
Torrey et al. (2009), USA | Cohort + MA (10 studies) | 168 + 88 cases 25 025 controls
| Cohort of 88 cases: Paternal age: >35 years: OR 1.35 (0.88–2.06) >40 years: OR 1.33 (0.75–2.37) >45 years: OR 1.32 (0.48–3.63) ≥55 years: MA: pooled OR 2.21 (1.46–3.37)
| NA | Matched for city of birth, season of birth and parental history of treatment for mental disorder | Low |
Tsuchiya et al. (2005), Japan | Case control | 99 cases, 381 controls | | Paternal age < 25 years | Adjusted for age and gender of the subject, parity, family history and maternal age. | Low |
Wang et al. (2015), Taiwan | Case series | 1297 cases | | Paternal age 21–24 years | Study of earlier onset among co-affected sib-pairs with the same familial predisposition. Adjusted for maternal age, gender, education in years and parental education
| Low |
Wu et al. (2012), China | Case control | | 351 patients with schizophrenia (167 males, 134 females) Paternal age: <25 years: OR 0.628 (0.350–1.127) 30–34 years: OR 2.660 (1.697–4.169) >35 years: OR 10.183 (4.772–21.729)
| Paternal age 25–29 years | Adjusted for participant´s sex, age and maternal age | Low |
Zammit et al. (2003), Sweden | Cohort | 2362 cases 50 087 individuals
| | Paternal age 15–24 years | Adjusted for maternal age, drug use, poor social integration and place of upbringing. | |
Fourteen of the original articles were included in a meta-analysis (Fig. 13). All of these studies adjusted for maternal age. Paternal age was categorized as <35, 35–39, 40–45, >45 and >50 years. A higher risk of schizophrenia was associated with increasing paternal age (pooled estimate 1.31, 95% CI 1.23–1.38).
Figure 13
Forest plot describing the association between paternal age and risk for schizophrenia/schizoaffective disorders in the offspring.
Conclusion: Higher paternal age is probably associated with an increased risk of schizophrenia in offspring. Moderate certainty of evidence (GRADE⊕⊕⊕○).
Other psychiatric disorders
Fifteen studies concentrated on other psychiatric conditions including attention deficit hyperactivity syndrome (ADHD) (three studies), eating disorders (two studies), psychosis (three studies), bipolar disorders (six studies), Tourette disorder (one study) and neurocognitive development (one study) (Supplementary Table SI, Table VI).
Table VIStudies on the association of paternal age with other psychiatric disorders in offspring
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Outcomes (Risk estimates)
. | Adjustments Reference group/Control
. |
---|
Adjustments
. |
---|
Original articles n = 15 |
Brown et al. (2013), USA | Case control study | | | Paternal age 20–29 years | Bipolar disorders Measured as 10 years increase in paternal age. Controls were matched on date of birth, sex and residency Adjusted for maternal age
| Low |
Burd et al. (1999b), USA | Case control study | | | Each additional year of paternal age decreased the risk of Tourette syndrome by 9.1% | | Low |
Chudal et al. (2014), Finland | Case control study | | Paternal age: >50 years AOR 2.84 (1.32–6.12) 30–34 years AOR 1.35 (1.06–1.72)
| Paternal age 25–29 years | | Medium |
Chudal et al. (2015), Finland | Case control study | 10 409 cases 39 125 controls
| Paternal age: <20 years AOR 1.55 (1.11–2.18) 20–24 years AOR 2.20 (1.07–1.34) 45–49 years AOR 1.26 (1.01–1.58) ≥50 years AOR 1.08 (0.73–1.58)
| Paternal age 25–29 years | ADHD in singleton births during 1991–2005, diagnosed 1995–2011 ADHD was associated with young fathers Adjusted for maternal age, paternal psychiatric history, maternal SES, maternal smoking during pregnancy, previous birth, birth weight for gestational age
| Medium |
D’Onofrio et al. (2014), Sweden | Cohort study | | | Paternal age 20–24 years | ADHD, bipolar disorders, psychosis Adjusted for maternal age, sex, year of birth, parental education, history of psychiatric hospitalization. Also sibling-comparison analyses
| High |
El-Saadi et al. (2004), Sweden and Australia | | | Paternal age: Denmark: 35–39 years AOR 1.14 (1.05–1.24) 50–54 years: AOR 1.33 (1.33–2.53) ≥35 years: Sweden: AOR 2.42 (1.19–4.89) Australia: AOR 0.77 (0.24–2.46)
| Paternal age 20–24 years | | Low to medium depending on study group |
Foutz and Mezuk (2015), USA | Cohort study | | Paternal age: 30–34 years: AOR 0,63 (0.25–1.60) ≥35 years: AOR 2.12 (1.08–4.16)
| Paternal age 25–29 years | Psychotic-like symptoms Adjusted for demographic characteristics, birth order, lifetime history of depression, anxiety and substance use disorders.
| Low |
Frans et al. (2008), Sweden | Case control study | 13 428 cases 67 140 controls
| Paternal age: 45–49 years OR 1.14 (1.00–1.30) 50–54 years OR 1.21 (1.00–1.48) >55 years OR 1.37 (1.02–1.84)
| Paternal age 20–24 years | | Medium |
Gillberg (1982), Sweden | Cohort study | 155 cases: Mental retardation 4 Psychosis 30 Psychogenic psychosis 2 Hyperkinetic disorders 3 Anorexia nervosa 5 Conduct disorders 38 Emotional disorders 64 Others 8 82 570 population
| Paternal age: No risk estimate
| NA | | Low |
Hvolgaard Mikkelsen et al. (2016), Denmark | Cohort study | 12 294 cases 943 785 singletons
| Paternal age: 31–35 years AHR 0.9 (0.77–1.05) ≥35 years AHR 0.74 (0.53–1.02)
| Paternal age 26–30 years | | High |
Javaras et al. (2017), Sweden | Cohort study | | Paternal age: Anorexia nervosa: 20–24 years AOR 0.91 (0.80–0.96) ≥45 years AOR 1.32 (1.14–1.53) Any eating disorder: 20–24 years AOR 0.93 (0.87–0.98) ≥45 years AOR 1.26 (1.13–1.40)
| Paternal age 25–29 years | Eating disorders (anorexia nervosa and any eating disorder). Adjusted for sex, birth order, maternal age, country of birth, parental highest education level, lifetime psychiatric and criminal history | High |
Lehrer et al. (2016), USA | Case control study | | | Paternal age 20–24 years | | Medium |
Menezes et al. (2010), Sweden | Cohort study | 493 cases 754 330 population
| Paternal age: 40–44 years HR 1.85 (1.04–3.30) 45–49 years HR 1.06 (0.39–2.83) >50 years HR 1.43 (0.43–4.76)
| Paternal age 21–24 years | Bipolar affective disorders (BPAD) Adjusted for maternal age, SES, family history of psychosis and education Risk of BPAD for each 10-years increase in paternal age
| Medium |
Racine et al. (2014), USA | Cohort study | 1722 female twins aged 8–17 years, 11 cases | Paternal age: No risk estimate.
| Paternal age ≥40 years was coded as reference group for t-test comparisons in categorical paternal age models | | Low |
Saha et al. (2009), Australia | Cohort study | 33 437 singletons | | Paternal age 20 years | Neurocognitive development Adjusted for maternal age, offspring sex, mother’s race, weeks of gestation, child’s age at testing, family and SES
| Medium |
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Outcomes (Risk estimates)
. | Adjustments Reference group/Control
. |
---|
Adjustments
. |
---|
Original articles n = 15 |
Brown et al. (2013), USA | Case control study | | | Paternal age 20–29 years | Bipolar disorders Measured as 10 years increase in paternal age. Controls were matched on date of birth, sex and residency Adjusted for maternal age
| Low |
Burd et al. (1999b), USA | Case control study | | | Each additional year of paternal age decreased the risk of Tourette syndrome by 9.1% | | Low |
Chudal et al. (2014), Finland | Case control study | | Paternal age: >50 years AOR 2.84 (1.32–6.12) 30–34 years AOR 1.35 (1.06–1.72)
| Paternal age 25–29 years | | Medium |
Chudal et al. (2015), Finland | Case control study | 10 409 cases 39 125 controls
| Paternal age: <20 years AOR 1.55 (1.11–2.18) 20–24 years AOR 2.20 (1.07–1.34) 45–49 years AOR 1.26 (1.01–1.58) ≥50 years AOR 1.08 (0.73–1.58)
| Paternal age 25–29 years | ADHD in singleton births during 1991–2005, diagnosed 1995–2011 ADHD was associated with young fathers Adjusted for maternal age, paternal psychiatric history, maternal SES, maternal smoking during pregnancy, previous birth, birth weight for gestational age
| Medium |
D’Onofrio et al. (2014), Sweden | Cohort study | | | Paternal age 20–24 years | ADHD, bipolar disorders, psychosis Adjusted for maternal age, sex, year of birth, parental education, history of psychiatric hospitalization. Also sibling-comparison analyses
| High |
El-Saadi et al. (2004), Sweden and Australia | | | Paternal age: Denmark: 35–39 years AOR 1.14 (1.05–1.24) 50–54 years: AOR 1.33 (1.33–2.53) ≥35 years: Sweden: AOR 2.42 (1.19–4.89) Australia: AOR 0.77 (0.24–2.46)
| Paternal age 20–24 years | | Low to medium depending on study group |
Foutz and Mezuk (2015), USA | Cohort study | | Paternal age: 30–34 years: AOR 0,63 (0.25–1.60) ≥35 years: AOR 2.12 (1.08–4.16)
| Paternal age 25–29 years | Psychotic-like symptoms Adjusted for demographic characteristics, birth order, lifetime history of depression, anxiety and substance use disorders.
| Low |
Frans et al. (2008), Sweden | Case control study | 13 428 cases 67 140 controls
| Paternal age: 45–49 years OR 1.14 (1.00–1.30) 50–54 years OR 1.21 (1.00–1.48) >55 years OR 1.37 (1.02–1.84)
| Paternal age 20–24 years | | Medium |
Gillberg (1982), Sweden | Cohort study | 155 cases: Mental retardation 4 Psychosis 30 Psychogenic psychosis 2 Hyperkinetic disorders 3 Anorexia nervosa 5 Conduct disorders 38 Emotional disorders 64 Others 8 82 570 population
| Paternal age: No risk estimate
| NA | | Low |
Hvolgaard Mikkelsen et al. (2016), Denmark | Cohort study | 12 294 cases 943 785 singletons
| Paternal age: 31–35 years AHR 0.9 (0.77–1.05) ≥35 years AHR 0.74 (0.53–1.02)
| Paternal age 26–30 years | | High |
Javaras et al. (2017), Sweden | Cohort study | | Paternal age: Anorexia nervosa: 20–24 years AOR 0.91 (0.80–0.96) ≥45 years AOR 1.32 (1.14–1.53) Any eating disorder: 20–24 years AOR 0.93 (0.87–0.98) ≥45 years AOR 1.26 (1.13–1.40)
| Paternal age 25–29 years | Eating disorders (anorexia nervosa and any eating disorder). Adjusted for sex, birth order, maternal age, country of birth, parental highest education level, lifetime psychiatric and criminal history | High |
Lehrer et al. (2016), USA | Case control study | | | Paternal age 20–24 years | | Medium |
Menezes et al. (2010), Sweden | Cohort study | 493 cases 754 330 population
| Paternal age: 40–44 years HR 1.85 (1.04–3.30) 45–49 years HR 1.06 (0.39–2.83) >50 years HR 1.43 (0.43–4.76)
| Paternal age 21–24 years | Bipolar affective disorders (BPAD) Adjusted for maternal age, SES, family history of psychosis and education Risk of BPAD for each 10-years increase in paternal age
| Medium |
Racine et al. (2014), USA | Cohort study | 1722 female twins aged 8–17 years, 11 cases | Paternal age: No risk estimate.
| Paternal age ≥40 years was coded as reference group for t-test comparisons in categorical paternal age models | | Low |
Saha et al. (2009), Australia | Cohort study | 33 437 singletons | | Paternal age 20 years | Neurocognitive development Adjusted for maternal age, offspring sex, mother’s race, weeks of gestation, child’s age at testing, family and SES
| Medium |
Table VIStudies on the association of paternal age with other psychiatric disorders in offspring
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Outcomes (Risk estimates)
. | Adjustments Reference group/Control
. |
---|
Adjustments
. |
---|
Original articles n = 15 |
Brown et al. (2013), USA | Case control study | | | Paternal age 20–29 years | Bipolar disorders Measured as 10 years increase in paternal age. Controls were matched on date of birth, sex and residency Adjusted for maternal age
| Low |
Burd et al. (1999b), USA | Case control study | | | Each additional year of paternal age decreased the risk of Tourette syndrome by 9.1% | | Low |
Chudal et al. (2014), Finland | Case control study | | Paternal age: >50 years AOR 2.84 (1.32–6.12) 30–34 years AOR 1.35 (1.06–1.72)
| Paternal age 25–29 years | | Medium |
Chudal et al. (2015), Finland | Case control study | 10 409 cases 39 125 controls
| Paternal age: <20 years AOR 1.55 (1.11–2.18) 20–24 years AOR 2.20 (1.07–1.34) 45–49 years AOR 1.26 (1.01–1.58) ≥50 years AOR 1.08 (0.73–1.58)
| Paternal age 25–29 years | ADHD in singleton births during 1991–2005, diagnosed 1995–2011 ADHD was associated with young fathers Adjusted for maternal age, paternal psychiatric history, maternal SES, maternal smoking during pregnancy, previous birth, birth weight for gestational age
| Medium |
D’Onofrio et al. (2014), Sweden | Cohort study | | | Paternal age 20–24 years | ADHD, bipolar disorders, psychosis Adjusted for maternal age, sex, year of birth, parental education, history of psychiatric hospitalization. Also sibling-comparison analyses
| High |
El-Saadi et al. (2004), Sweden and Australia | | | Paternal age: Denmark: 35–39 years AOR 1.14 (1.05–1.24) 50–54 years: AOR 1.33 (1.33–2.53) ≥35 years: Sweden: AOR 2.42 (1.19–4.89) Australia: AOR 0.77 (0.24–2.46)
| Paternal age 20–24 years | | Low to medium depending on study group |
Foutz and Mezuk (2015), USA | Cohort study | | Paternal age: 30–34 years: AOR 0,63 (0.25–1.60) ≥35 years: AOR 2.12 (1.08–4.16)
| Paternal age 25–29 years | Psychotic-like symptoms Adjusted for demographic characteristics, birth order, lifetime history of depression, anxiety and substance use disorders.
| Low |
Frans et al. (2008), Sweden | Case control study | 13 428 cases 67 140 controls
| Paternal age: 45–49 years OR 1.14 (1.00–1.30) 50–54 years OR 1.21 (1.00–1.48) >55 years OR 1.37 (1.02–1.84)
| Paternal age 20–24 years | | Medium |
Gillberg (1982), Sweden | Cohort study | 155 cases: Mental retardation 4 Psychosis 30 Psychogenic psychosis 2 Hyperkinetic disorders 3 Anorexia nervosa 5 Conduct disorders 38 Emotional disorders 64 Others 8 82 570 population
| Paternal age: No risk estimate
| NA | | Low |
Hvolgaard Mikkelsen et al. (2016), Denmark | Cohort study | 12 294 cases 943 785 singletons
| Paternal age: 31–35 years AHR 0.9 (0.77–1.05) ≥35 years AHR 0.74 (0.53–1.02)
| Paternal age 26–30 years | | High |
Javaras et al. (2017), Sweden | Cohort study | | Paternal age: Anorexia nervosa: 20–24 years AOR 0.91 (0.80–0.96) ≥45 years AOR 1.32 (1.14–1.53) Any eating disorder: 20–24 years AOR 0.93 (0.87–0.98) ≥45 years AOR 1.26 (1.13–1.40)
| Paternal age 25–29 years | Eating disorders (anorexia nervosa and any eating disorder). Adjusted for sex, birth order, maternal age, country of birth, parental highest education level, lifetime psychiatric and criminal history | High |
Lehrer et al. (2016), USA | Case control study | | | Paternal age 20–24 years | | Medium |
Menezes et al. (2010), Sweden | Cohort study | 493 cases 754 330 population
| Paternal age: 40–44 years HR 1.85 (1.04–3.30) 45–49 years HR 1.06 (0.39–2.83) >50 years HR 1.43 (0.43–4.76)
| Paternal age 21–24 years | Bipolar affective disorders (BPAD) Adjusted for maternal age, SES, family history of psychosis and education Risk of BPAD for each 10-years increase in paternal age
| Medium |
Racine et al. (2014), USA | Cohort study | 1722 female twins aged 8–17 years, 11 cases | Paternal age: No risk estimate.
| Paternal age ≥40 years was coded as reference group for t-test comparisons in categorical paternal age models | | Low |
Saha et al. (2009), Australia | Cohort study | 33 437 singletons | | Paternal age 20 years | Neurocognitive development Adjusted for maternal age, offspring sex, mother’s race, weeks of gestation, child’s age at testing, family and SES
| Medium |
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Outcomes
. | Quality
. |
---|
Comment
. |
---|
Outcomes (Risk estimates)
. | Adjustments Reference group/Control
. |
---|
Adjustments
. |
---|
Original articles n = 15 |
Brown et al. (2013), USA | Case control study | | | Paternal age 20–29 years | Bipolar disorders Measured as 10 years increase in paternal age. Controls were matched on date of birth, sex and residency Adjusted for maternal age
| Low |
Burd et al. (1999b), USA | Case control study | | | Each additional year of paternal age decreased the risk of Tourette syndrome by 9.1% | | Low |
Chudal et al. (2014), Finland | Case control study | | Paternal age: >50 years AOR 2.84 (1.32–6.12) 30–34 years AOR 1.35 (1.06–1.72)
| Paternal age 25–29 years | | Medium |
Chudal et al. (2015), Finland | Case control study | 10 409 cases 39 125 controls
| Paternal age: <20 years AOR 1.55 (1.11–2.18) 20–24 years AOR 2.20 (1.07–1.34) 45–49 years AOR 1.26 (1.01–1.58) ≥50 years AOR 1.08 (0.73–1.58)
| Paternal age 25–29 years | ADHD in singleton births during 1991–2005, diagnosed 1995–2011 ADHD was associated with young fathers Adjusted for maternal age, paternal psychiatric history, maternal SES, maternal smoking during pregnancy, previous birth, birth weight for gestational age
| Medium |
D’Onofrio et al. (2014), Sweden | Cohort study | | | Paternal age 20–24 years | ADHD, bipolar disorders, psychosis Adjusted for maternal age, sex, year of birth, parental education, history of psychiatric hospitalization. Also sibling-comparison analyses
| High |
El-Saadi et al. (2004), Sweden and Australia | | | Paternal age: Denmark: 35–39 years AOR 1.14 (1.05–1.24) 50–54 years: AOR 1.33 (1.33–2.53) ≥35 years: Sweden: AOR 2.42 (1.19–4.89) Australia: AOR 0.77 (0.24–2.46)
| Paternal age 20–24 years | | Low to medium depending on study group |
Foutz and Mezuk (2015), USA | Cohort study | | Paternal age: 30–34 years: AOR 0,63 (0.25–1.60) ≥35 years: AOR 2.12 (1.08–4.16)
| Paternal age 25–29 years | Psychotic-like symptoms Adjusted for demographic characteristics, birth order, lifetime history of depression, anxiety and substance use disorders.
| Low |
Frans et al. (2008), Sweden | Case control study | 13 428 cases 67 140 controls
| Paternal age: 45–49 years OR 1.14 (1.00–1.30) 50–54 years OR 1.21 (1.00–1.48) >55 years OR 1.37 (1.02–1.84)
| Paternal age 20–24 years | | Medium |
Gillberg (1982), Sweden | Cohort study | 155 cases: Mental retardation 4 Psychosis 30 Psychogenic psychosis 2 Hyperkinetic disorders 3 Anorexia nervosa 5 Conduct disorders 38 Emotional disorders 64 Others 8 82 570 population
| Paternal age: No risk estimate
| NA | | Low |
Hvolgaard Mikkelsen et al. (2016), Denmark | Cohort study | 12 294 cases 943 785 singletons
| Paternal age: 31–35 years AHR 0.9 (0.77–1.05) ≥35 years AHR 0.74 (0.53–1.02)
| Paternal age 26–30 years | | High |
Javaras et al. (2017), Sweden | Cohort study | | Paternal age: Anorexia nervosa: 20–24 years AOR 0.91 (0.80–0.96) ≥45 years AOR 1.32 (1.14–1.53) Any eating disorder: 20–24 years AOR 0.93 (0.87–0.98) ≥45 years AOR 1.26 (1.13–1.40)
| Paternal age 25–29 years | Eating disorders (anorexia nervosa and any eating disorder). Adjusted for sex, birth order, maternal age, country of birth, parental highest education level, lifetime psychiatric and criminal history | High |
Lehrer et al. (2016), USA | Case control study | | | Paternal age 20–24 years | | Medium |
Menezes et al. (2010), Sweden | Cohort study | 493 cases 754 330 population
| Paternal age: 40–44 years HR 1.85 (1.04–3.30) 45–49 years HR 1.06 (0.39–2.83) >50 years HR 1.43 (0.43–4.76)
| Paternal age 21–24 years | Bipolar affective disorders (BPAD) Adjusted for maternal age, SES, family history of psychosis and education Risk of BPAD for each 10-years increase in paternal age
| Medium |
Racine et al. (2014), USA | Cohort study | 1722 female twins aged 8–17 years, 11 cases | Paternal age: No risk estimate.
| Paternal age ≥40 years was coded as reference group for t-test comparisons in categorical paternal age models | | Low |
Saha et al. (2009), Australia | Cohort study | 33 437 singletons | | Paternal age 20 years | Neurocognitive development Adjusted for maternal age, offspring sex, mother’s race, weeks of gestation, child’s age at testing, family and SES
| Medium |
ADHD Two studies (D’Onofrio et al., 2014; Hvolgaard Mikkelsen et al., 2016) were of high and one of medium quality (Chudal et al., 2015). Chudal et al. (2015) reported an association between younger fathers and ADHD (highest risk associated with paternal age 20–24 years). Another study (D’Onofrio et al., 2014) reported an association of ADHD with advanced paternal age, and the third study (Hvolgaard Mikkelsen et al., 2016) found that there was a higher risk of ADHD if both parents were very young.
Eating disorders Two studies reported on eating disorders (one of high and one of low quality) (Racine et al., 2014; Javaras et al., 2017). The high quality study reported an association between advanced paternal age and eating disorders and also an association with anorexia nervosa (Javaras et al., 2017).
Bipolar disorders Six studies have assessed the risk of bipolar disorders in offspring in relation to advanced paternal age, two study of high quality (Brown et al., 2013; D’Onofrio et al., 2014) three of medium quality (Frans et al., 2008; Chudal et al., 2014; Lehrer et al., 2016) and one of low quality (Menezes et al., 2010). Both Brown et al. (2013) and D’Onofrio et al. (2014) showed that advanced paternal age was a risk factor for bipolar disorders in offspring.
Psychosis and psychotic-like symptoms Three studies, including two case control studies of low quality (Gillberg, 1982; Foutz and Mezuk, 2015) and one study (El-Saadi et al., 2004) which reported results from three different countries, assessed the association between paternal age and psychosis and psychotic-like symptoms in offspring. Two of the studies found an association between advanced paternal age and psychosis (El-Saadi et al., 2004; Foutz and Mezuk, 2015).
Conclusion: It is uncertain whether paternal age is associated with an increased risk of other psychiatric conditions. Very low certainty of evidence (GRADE ⊕○○○)
Paternal BMI, height and/or weight at childbirth and short-term outcomes for offspring
Obstetric outcomes
Altogether 13 cohort studies (mostly of medium quality) have evaluated the effect of paternal BMI, height, and/or weight on obstetric outcomes, in most cases on BW of infants (Supplementary Table SII, Table VII). All studies included in the systematic review had adjusted for maternal factors such as maternal height and BMI. In nine studies the influence of paternal height on BW of the children was studied. In all studies the father´s height correlated significantly with BW of the offspring. The effects of BMI, and the weight of the father at the time of conception, or at the beginning of the pregnancy, on neonatal BW were less clear. In one study from 2012, paternal BMI correlated significantly with BW of the newborn, and biparietal diameter, head circumference and pectoral diameter in male offspring (Chen et al., 2012). However, three of six studies did not find any association between paternal BMI and BW of the babies (Table III). Four studies evaluated the correlation between paternal weight at conception and child BW. In three of these reports no association was found (Wilcox et al., 1995; To et al., 1998; Nahum and Stanislaw, 2003). Two studies compared paternal and child BW, with conflicting results (Klebanoff et al., 1998; L’Abee et al., 2011).
Table VIIStudies on the association of paternal BMI, height and weight with obstetric outcomes in offspring.
Author, year, country
. | Study design
. | Number of children
. | Results
. | Outcomes
. | Quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Original articles n = 13 |
Cawley et al. (1954), UK | Cohort study | 1028 children | The height of the fathers was divided into six groups (under 60 inches up to 72 inches and over). BW of the child increased with increased height of father (6.73, 6.91, 7.31, 7.35, 7.55, and 7.74 pounds respectively) | | Medium |
Chen et al. (2012), China | Cohort study | 889 children; 492 boys and 407 girls | Association between paternal BMI and foetal growth of male offspring: BW (P = 0.013), biparietal diameter (P = 0.001), head circumference (P = 0.006), abdominal circumference (P = 0.003) and pectoral diameter (P = 0.043). Paternal BMI was not associated with foetal growth of female offspring.
| BW, newborn´s body shape and endocrine system Multivariable regression analysis considering maternal BMI, paternal and maternal age, hypertension during pregnancy, maternal glycated serum protein, parity and gestational age as confounding factors
| Low |
Klebanoff et al. (1998), Denmark | Cohort study | | Paternal BW was associated with infant BW (P = 0.002). Association between paternal adult height and infant BW (P = 0.088) Association between paternal BMI and infant BW (P = 0.049)
| BW Adjusted for maternal BW; maternal adult height, weight, hypertension, diabetes, smoking, education, employment status, and location of residence; child´s birth order and gender; other paternal characteristics
| Medium |
L’Abee et al. (2011), the Netherlands | Cohort study | 2947 singletons born 2006–2007 | Paternal BMI and paternal BW were not independent predictors for BW of the offspring | | Medium |
Lawlor et al. (2007) Australia | Cohort study | 7223 women and their offspring | Paternal pre-pregnancy BMI: borderline significantly positive association with birth weight standardized for sex and gestational age (regression coefficient 0.03) | | Medium |
Magnus et al. (1984), Norway | Cohort study | 3130 families | | | Medium |
Morrison et al. (1991), Australia | Cohort study | 5989 children | Paternal height was significantly associated with BW (P < 0.0007) The increase of the BW was up to 152 g with increased height of the father (ranging from 165 cm to 184 cm). Paternal BMI had no significant effect on the BW of the child
| | Medium |
Mutsaerts et al. (2014), Australia | Cohort study | 2264 children | | | Medium |
Nahum and Stanislaw (2003), USA | Cohort study | 241 children | Association between paternal height and child BW (P = 0.02) The addition in term BW attributable to each unit increase in paternal height was 10 g/cm No significant association between paternal weight and child BW
| | Low |
Pritchard et al. (1983), UK | Cohort study | 5834 children | | | High |
To et al. (1998), China | Cohort study | 355 children born at term | Association between paternal height and child BW (P < 0.01) No association between paternal weight and child (P = 0.052) No association between paternal BMI and child BW (P = 0.329)
| | Medium |
Wilcox et al. (1995), UK | Cohort study | 571 children | | | |
Winikoff and Debrovner (1981), USA | Cohort study | 259 children | Paternal height was significantly associated with variations in child BW (P < 0.05) | BW Adjusted for maternal height, paternal weight, maternal pre-pregnancy weight, weight during pregnancy
| Medium |
Author, year, country
. | Study design
. | Number of children
. | Results
. | Outcomes
. | Quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Original articles n = 13 |
Cawley et al. (1954), UK | Cohort study | 1028 children | The height of the fathers was divided into six groups (under 60 inches up to 72 inches and over). BW of the child increased with increased height of father (6.73, 6.91, 7.31, 7.35, 7.55, and 7.74 pounds respectively) | | Medium |
Chen et al. (2012), China | Cohort study | 889 children; 492 boys and 407 girls | Association between paternal BMI and foetal growth of male offspring: BW (P = 0.013), biparietal diameter (P = 0.001), head circumference (P = 0.006), abdominal circumference (P = 0.003) and pectoral diameter (P = 0.043). Paternal BMI was not associated with foetal growth of female offspring.
| BW, newborn´s body shape and endocrine system Multivariable regression analysis considering maternal BMI, paternal and maternal age, hypertension during pregnancy, maternal glycated serum protein, parity and gestational age as confounding factors
| Low |
Klebanoff et al. (1998), Denmark | Cohort study | | Paternal BW was associated with infant BW (P = 0.002). Association between paternal adult height and infant BW (P = 0.088) Association between paternal BMI and infant BW (P = 0.049)
| BW Adjusted for maternal BW; maternal adult height, weight, hypertension, diabetes, smoking, education, employment status, and location of residence; child´s birth order and gender; other paternal characteristics
| Medium |
L’Abee et al. (2011), the Netherlands | Cohort study | 2947 singletons born 2006–2007 | Paternal BMI and paternal BW were not independent predictors for BW of the offspring | | Medium |
Lawlor et al. (2007) Australia | Cohort study | 7223 women and their offspring | Paternal pre-pregnancy BMI: borderline significantly positive association with birth weight standardized for sex and gestational age (regression coefficient 0.03) | | Medium |
Magnus et al. (1984), Norway | Cohort study | 3130 families | | | Medium |
Morrison et al. (1991), Australia | Cohort study | 5989 children | Paternal height was significantly associated with BW (P < 0.0007) The increase of the BW was up to 152 g with increased height of the father (ranging from 165 cm to 184 cm). Paternal BMI had no significant effect on the BW of the child
| | Medium |
Mutsaerts et al. (2014), Australia | Cohort study | 2264 children | | | Medium |
Nahum and Stanislaw (2003), USA | Cohort study | 241 children | Association between paternal height and child BW (P = 0.02) The addition in term BW attributable to each unit increase in paternal height was 10 g/cm No significant association between paternal weight and child BW
| | Low |
Pritchard et al. (1983), UK | Cohort study | 5834 children | | | High |
To et al. (1998), China | Cohort study | 355 children born at term | Association between paternal height and child BW (P < 0.01) No association between paternal weight and child (P = 0.052) No association between paternal BMI and child BW (P = 0.329)
| | Medium |
Wilcox et al. (1995), UK | Cohort study | 571 children | | | |
Winikoff and Debrovner (1981), USA | Cohort study | 259 children | Paternal height was significantly associated with variations in child BW (P < 0.05) | BW Adjusted for maternal height, paternal weight, maternal pre-pregnancy weight, weight during pregnancy
| Medium |
Table VIIStudies on the association of paternal BMI, height and weight with obstetric outcomes in offspring.
Author, year, country
. | Study design
. | Number of children
. | Results
. | Outcomes
. | Quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Original articles n = 13 |
Cawley et al. (1954), UK | Cohort study | 1028 children | The height of the fathers was divided into six groups (under 60 inches up to 72 inches and over). BW of the child increased with increased height of father (6.73, 6.91, 7.31, 7.35, 7.55, and 7.74 pounds respectively) | | Medium |
Chen et al. (2012), China | Cohort study | 889 children; 492 boys and 407 girls | Association between paternal BMI and foetal growth of male offspring: BW (P = 0.013), biparietal diameter (P = 0.001), head circumference (P = 0.006), abdominal circumference (P = 0.003) and pectoral diameter (P = 0.043). Paternal BMI was not associated with foetal growth of female offspring.
| BW, newborn´s body shape and endocrine system Multivariable regression analysis considering maternal BMI, paternal and maternal age, hypertension during pregnancy, maternal glycated serum protein, parity and gestational age as confounding factors
| Low |
Klebanoff et al. (1998), Denmark | Cohort study | | Paternal BW was associated with infant BW (P = 0.002). Association between paternal adult height and infant BW (P = 0.088) Association between paternal BMI and infant BW (P = 0.049)
| BW Adjusted for maternal BW; maternal adult height, weight, hypertension, diabetes, smoking, education, employment status, and location of residence; child´s birth order and gender; other paternal characteristics
| Medium |
L’Abee et al. (2011), the Netherlands | Cohort study | 2947 singletons born 2006–2007 | Paternal BMI and paternal BW were not independent predictors for BW of the offspring | | Medium |
Lawlor et al. (2007) Australia | Cohort study | 7223 women and their offspring | Paternal pre-pregnancy BMI: borderline significantly positive association with birth weight standardized for sex and gestational age (regression coefficient 0.03) | | Medium |
Magnus et al. (1984), Norway | Cohort study | 3130 families | | | Medium |
Morrison et al. (1991), Australia | Cohort study | 5989 children | Paternal height was significantly associated with BW (P < 0.0007) The increase of the BW was up to 152 g with increased height of the father (ranging from 165 cm to 184 cm). Paternal BMI had no significant effect on the BW of the child
| | Medium |
Mutsaerts et al. (2014), Australia | Cohort study | 2264 children | | | Medium |
Nahum and Stanislaw (2003), USA | Cohort study | 241 children | Association between paternal height and child BW (P = 0.02) The addition in term BW attributable to each unit increase in paternal height was 10 g/cm No significant association between paternal weight and child BW
| | Low |
Pritchard et al. (1983), UK | Cohort study | 5834 children | | | High |
To et al. (1998), China | Cohort study | 355 children born at term | Association between paternal height and child BW (P < 0.01) No association between paternal weight and child (P = 0.052) No association between paternal BMI and child BW (P = 0.329)
| | Medium |
Wilcox et al. (1995), UK | Cohort study | 571 children | | | |
Winikoff and Debrovner (1981), USA | Cohort study | 259 children | Paternal height was significantly associated with variations in child BW (P < 0.05) | BW Adjusted for maternal height, paternal weight, maternal pre-pregnancy weight, weight during pregnancy
| Medium |
Author, year, country
. | Study design
. | Number of children
. | Results
. | Outcomes
. | Quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Original articles n = 13 |
Cawley et al. (1954), UK | Cohort study | 1028 children | The height of the fathers was divided into six groups (under 60 inches up to 72 inches and over). BW of the child increased with increased height of father (6.73, 6.91, 7.31, 7.35, 7.55, and 7.74 pounds respectively) | | Medium |
Chen et al. (2012), China | Cohort study | 889 children; 492 boys and 407 girls | Association between paternal BMI and foetal growth of male offspring: BW (P = 0.013), biparietal diameter (P = 0.001), head circumference (P = 0.006), abdominal circumference (P = 0.003) and pectoral diameter (P = 0.043). Paternal BMI was not associated with foetal growth of female offspring.
| BW, newborn´s body shape and endocrine system Multivariable regression analysis considering maternal BMI, paternal and maternal age, hypertension during pregnancy, maternal glycated serum protein, parity and gestational age as confounding factors
| Low |
Klebanoff et al. (1998), Denmark | Cohort study | | Paternal BW was associated with infant BW (P = 0.002). Association between paternal adult height and infant BW (P = 0.088) Association between paternal BMI and infant BW (P = 0.049)
| BW Adjusted for maternal BW; maternal adult height, weight, hypertension, diabetes, smoking, education, employment status, and location of residence; child´s birth order and gender; other paternal characteristics
| Medium |
L’Abee et al. (2011), the Netherlands | Cohort study | 2947 singletons born 2006–2007 | Paternal BMI and paternal BW were not independent predictors for BW of the offspring | | Medium |
Lawlor et al. (2007) Australia | Cohort study | 7223 women and their offspring | Paternal pre-pregnancy BMI: borderline significantly positive association with birth weight standardized for sex and gestational age (regression coefficient 0.03) | | Medium |
Magnus et al. (1984), Norway | Cohort study | 3130 families | | | Medium |
Morrison et al. (1991), Australia | Cohort study | 5989 children | Paternal height was significantly associated with BW (P < 0.0007) The increase of the BW was up to 152 g with increased height of the father (ranging from 165 cm to 184 cm). Paternal BMI had no significant effect on the BW of the child
| | Medium |
Mutsaerts et al. (2014), Australia | Cohort study | 2264 children | | | Medium |
Nahum and Stanislaw (2003), USA | Cohort study | 241 children | Association between paternal height and child BW (P = 0.02) The addition in term BW attributable to each unit increase in paternal height was 10 g/cm No significant association between paternal weight and child BW
| | Low |
Pritchard et al. (1983), UK | Cohort study | 5834 children | | | High |
To et al. (1998), China | Cohort study | 355 children born at term | Association between paternal height and child BW (P < 0.01) No association between paternal weight and child (P = 0.052) No association between paternal BMI and child BW (P = 0.329)
| | Medium |
Wilcox et al. (1995), UK | Cohort study | 571 children | | | |
Winikoff and Debrovner (1981), USA | Cohort study | 259 children | Paternal height was significantly associated with variations in child BW (P < 0.05) | BW Adjusted for maternal height, paternal weight, maternal pre-pregnancy weight, weight during pregnancy
| Medium |
Conclusion: Paternal height is probably associated with BW of the offspring. Moderate certainty of evidence (GRADE⊕⊕⊕○). There may be little or no association between paternal BMI/paternal weight and the BW of the offspring. Low quality of evidence (GRADE⊕⊕○○).
Paternal BMI, height and/or weight at childbirth and long-term outcomes for offspring
Obesity
Paternal anthropometric measurements (BMI, height and/or weight) available at the time of the child’s birth were studied in association with childhood outcomes in 13 cohort studies (nine medium and four high quality) and in one medium quality case control study (Supplementary Table SII, Table VIII). In two of the studies paternal height and weight were measured (Durmus et al., 2013; Heppe et al., 2013) and in other studies this information was obtained from questionnaires or records. The outcome was BMI, body fat and/or weight in 11 studies. Paternal anthropometrics at the time of the child’s birth were associated with offspring BMI, weight and/or body fat mass in all studies.
Table VIIIStudies on the association of paternal BMI, height and weight with long-term outcomes in offspring
Author, year, country
. | Study design
. | Number of children
. | Results
. | Outcomes
. | Quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Original studies n = 14 |
Catalano et al. (2009), USA | Case control study | | Paternal weight at the time birth was greater in children in tertile 3 of weight percentiles compared to children in tertile 1 at follow-up at 8.8 ± 1.8 years No difference in paternal BMI at the time of child’s birth in relation to tertiles of percentage body fat of the child
| Childhood weight and body fat (measured by dual energy X-ray absorptiometry) at follow-up Reference: Centers for Disease Control and Prevention (CDC) weight and body fat percentiles Maternal obstetrical data, paternal anthropometric data and neonatal birth data was included to best determine which combination of perinatal factors best modelled the risk of adiposity in child Maternal pre-pregnancy BMI was the strongest predictor of childhood obesity
| Medium |
Cawley et al. (1954), UK | Cohort study | 1028 children | Infant weight was more highly correlated with height of mother than father. Correlation of infant height and weight at 24 months; mother 0.21, father 0.13
| Weight of 625 children with observations at all intervals (6, 9, 12 and 24 months) Adjusted for maternal height
| Medium |
Daraki et al. (2017), Greece | Cohort study | 772 children | Paternal obesity not associated with child neurodevelopment at 4 years of age | | Medium |
Davey Smith et al. (2007), UK | Cohort study | 4654 children | The association between paternal BMI and offspring BMI at 7.5 years of age:0.202 standardised age and sex adjusted coefficient (0.175–0.229), similar to maternal BMI | Childhood BMI Standardised regression coefficients age and sex adjusted Sensitivity analysis for non-paternity performed Maternal and paternal BMI were included in the same model.
| High |
Durmus et al. (2011), The Netherlands | Cohort study | 5674 children | Pre-pregnancy paternal BMI was strongly associated with childhood overweight at the age of 4 years The main effects of maternal BMI on childhood BMI were stronger than the main effects of paternal BMI (P < 0.001; and P = 0.013, respectively) As compared to children from parents with normal BMI, children from two obese parents had an increased risk of overweight at the age of years, OR 6.52 (3.44–12.38)
| Childhood height, weight and BMI. Maternal BMI had a significantly stronger effect on childhood BMI Adjusted for maternal BMI
| High |
Heppe et al. (2013), The Netherlands | Cohort study | 3610 children | | | High |
Jaaskelainen et al. (2011), Finland | Cohort study (NFBC 1986) | 4788 children | Paternal pre-pregnancy obesity strongly predicted overweight: At 16 years of age: Father–son OR 3.17 (1.70–5.92) Father–daughter OR 5.58 (3.09–10.07) If both parents obese, overweight of the child at 16 years: Sons OR 5.66 (3.12–10.27) Daughters OR 14.84 (7.41–29.73)
| | High |
Lawlor et al. (2007), Australia | Cohort study | 7223 children | The increase in standardized offspring BMI at age 14 for a one SD increase in paternal BMI was 0.239 SD (0.197–0.282) | | Medium |
Lawlor et al. (2008), UK | Cohort study | 4091 children | As assessed at 9 to 11 years of age, mean difference in offspring sex- and age-standardized fat mass z-score per 1 SD BMI 0.24 (0.22–0.26) for maternal BMI versus 0.13 (0.11–0.15) for paternal BMI | Offspring fat and lean mass (measured by dual energy X-ray absorptiometry) Adjusted for maternal BMI Maternal effect size association was larger
| Medium |
Linabery et al. (2013), USA | Cohort study | 912 children | Infants of obese fathers had BMI growth curves distinct from those of normal weight fathers. The p value for the global association between paternal BMI category and infant BMI growth curves (birth-3.5 years) from joint mixed effect model was 0.02 | Infant BMI Maternal BMI has a stronger influence on BMI growth than paternal BMI Missing exposure (11% maternal and 26% paternal BMIs) and covariate data were assumed to be missing at random and imputed, outcomes were not imputed Adjusted for maternal BMI in the joint model
| Medium |
O’Callaghan et al. (1997), Australia | Cohort study | 4062 children | Paternal BMI is independent predictor of severe and moderate obesity at 5 years of age. Paternal BMI percentiles 85–94: Severe obesity RR 2.8 (1.8–4.5) Moderate obesity RR 1.0 (0.6–1.5) Paternal BMI percentiles >95: Severe obesity RR 2.0 (1.1–3.6) Moderate obesity RR 2.1 (1.4–3.3)
| | Medium |
Reilly et al. (2005), UK | Cohort study | 7758 children | Paternal obesity was associated with the risk of obesity in children at 7 years of age. Final model AOR: Father (BMI > 30) 2.54 (1.72–3.75) compared to both parents with BMI < 30. As compared to children from parents with normal BMI, children from two obese parents had an increased risk of overweight at the age of 4 years: OR 6.52 (3.44–12.38)
| | Medium |
Suren et al. (2014), Norway | Cohort study | 92 909 children | ASD in children at the age of 4.0–13.1 (mean 7.4) years: Paternal BMI > 30: versus BMI < 25 AOR 1.73 (1.07–2.82) Asperger disorder in children aged ≥7 years: Paternal BMI > 30 versus BMI < 25 AOR 2.01(1.13–3.57)
| | Medium |
Yeung et al. (2017), USA | Cohort study | 4821 children | Increased risk of failing the personal-social domain in children up to 3 years of age Paternal BMI > 30 compared with children of normal weight fathers AOR 1.71 (1.08–2.70) Children whose parents both had BMI ≥35 were likely to additionally fail the problem-solving domain
| | Medium |
Author, year, country
. | Study design
. | Number of children
. | Results
. | Outcomes
. | Quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Original studies n = 14 |
Catalano et al. (2009), USA | Case control study | | Paternal weight at the time birth was greater in children in tertile 3 of weight percentiles compared to children in tertile 1 at follow-up at 8.8 ± 1.8 years No difference in paternal BMI at the time of child’s birth in relation to tertiles of percentage body fat of the child
| Childhood weight and body fat (measured by dual energy X-ray absorptiometry) at follow-up Reference: Centers for Disease Control and Prevention (CDC) weight and body fat percentiles Maternal obstetrical data, paternal anthropometric data and neonatal birth data was included to best determine which combination of perinatal factors best modelled the risk of adiposity in child Maternal pre-pregnancy BMI was the strongest predictor of childhood obesity
| Medium |
Cawley et al. (1954), UK | Cohort study | 1028 children | Infant weight was more highly correlated with height of mother than father. Correlation of infant height and weight at 24 months; mother 0.21, father 0.13
| Weight of 625 children with observations at all intervals (6, 9, 12 and 24 months) Adjusted for maternal height
| Medium |
Daraki et al. (2017), Greece | Cohort study | 772 children | Paternal obesity not associated with child neurodevelopment at 4 years of age | | Medium |
Davey Smith et al. (2007), UK | Cohort study | 4654 children | The association between paternal BMI and offspring BMI at 7.5 years of age:0.202 standardised age and sex adjusted coefficient (0.175–0.229), similar to maternal BMI | Childhood BMI Standardised regression coefficients age and sex adjusted Sensitivity analysis for non-paternity performed Maternal and paternal BMI were included in the same model.
| High |
Durmus et al. (2011), The Netherlands | Cohort study | 5674 children | Pre-pregnancy paternal BMI was strongly associated with childhood overweight at the age of 4 years The main effects of maternal BMI on childhood BMI were stronger than the main effects of paternal BMI (P < 0.001; and P = 0.013, respectively) As compared to children from parents with normal BMI, children from two obese parents had an increased risk of overweight at the age of years, OR 6.52 (3.44–12.38)
| Childhood height, weight and BMI. Maternal BMI had a significantly stronger effect on childhood BMI Adjusted for maternal BMI
| High |
Heppe et al. (2013), The Netherlands | Cohort study | 3610 children | | | High |
Jaaskelainen et al. (2011), Finland | Cohort study (NFBC 1986) | 4788 children | Paternal pre-pregnancy obesity strongly predicted overweight: At 16 years of age: Father–son OR 3.17 (1.70–5.92) Father–daughter OR 5.58 (3.09–10.07) If both parents obese, overweight of the child at 16 years: Sons OR 5.66 (3.12–10.27) Daughters OR 14.84 (7.41–29.73)
| | High |
Lawlor et al. (2007), Australia | Cohort study | 7223 children | The increase in standardized offspring BMI at age 14 for a one SD increase in paternal BMI was 0.239 SD (0.197–0.282) | | Medium |
Lawlor et al. (2008), UK | Cohort study | 4091 children | As assessed at 9 to 11 years of age, mean difference in offspring sex- and age-standardized fat mass z-score per 1 SD BMI 0.24 (0.22–0.26) for maternal BMI versus 0.13 (0.11–0.15) for paternal BMI | Offspring fat and lean mass (measured by dual energy X-ray absorptiometry) Adjusted for maternal BMI Maternal effect size association was larger
| Medium |
Linabery et al. (2013), USA | Cohort study | 912 children | Infants of obese fathers had BMI growth curves distinct from those of normal weight fathers. The p value for the global association between paternal BMI category and infant BMI growth curves (birth-3.5 years) from joint mixed effect model was 0.02 | Infant BMI Maternal BMI has a stronger influence on BMI growth than paternal BMI Missing exposure (11% maternal and 26% paternal BMIs) and covariate data were assumed to be missing at random and imputed, outcomes were not imputed Adjusted for maternal BMI in the joint model
| Medium |
O’Callaghan et al. (1997), Australia | Cohort study | 4062 children | Paternal BMI is independent predictor of severe and moderate obesity at 5 years of age. Paternal BMI percentiles 85–94: Severe obesity RR 2.8 (1.8–4.5) Moderate obesity RR 1.0 (0.6–1.5) Paternal BMI percentiles >95: Severe obesity RR 2.0 (1.1–3.6) Moderate obesity RR 2.1 (1.4–3.3)
| | Medium |
Reilly et al. (2005), UK | Cohort study | 7758 children | Paternal obesity was associated with the risk of obesity in children at 7 years of age. Final model AOR: Father (BMI > 30) 2.54 (1.72–3.75) compared to both parents with BMI < 30. As compared to children from parents with normal BMI, children from two obese parents had an increased risk of overweight at the age of 4 years: OR 6.52 (3.44–12.38)
| | Medium |
Suren et al. (2014), Norway | Cohort study | 92 909 children | ASD in children at the age of 4.0–13.1 (mean 7.4) years: Paternal BMI > 30: versus BMI < 25 AOR 1.73 (1.07–2.82) Asperger disorder in children aged ≥7 years: Paternal BMI > 30 versus BMI < 25 AOR 2.01(1.13–3.57)
| | Medium |
Yeung et al. (2017), USA | Cohort study | 4821 children | Increased risk of failing the personal-social domain in children up to 3 years of age Paternal BMI > 30 compared with children of normal weight fathers AOR 1.71 (1.08–2.70) Children whose parents both had BMI ≥35 were likely to additionally fail the problem-solving domain
| | Medium |
Table VIIIStudies on the association of paternal BMI, height and weight with long-term outcomes in offspring
Author, year, country
. | Study design
. | Number of children
. | Results
. | Outcomes
. | Quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Original studies n = 14 |
Catalano et al. (2009), USA | Case control study | | Paternal weight at the time birth was greater in children in tertile 3 of weight percentiles compared to children in tertile 1 at follow-up at 8.8 ± 1.8 years No difference in paternal BMI at the time of child’s birth in relation to tertiles of percentage body fat of the child
| Childhood weight and body fat (measured by dual energy X-ray absorptiometry) at follow-up Reference: Centers for Disease Control and Prevention (CDC) weight and body fat percentiles Maternal obstetrical data, paternal anthropometric data and neonatal birth data was included to best determine which combination of perinatal factors best modelled the risk of adiposity in child Maternal pre-pregnancy BMI was the strongest predictor of childhood obesity
| Medium |
Cawley et al. (1954), UK | Cohort study | 1028 children | Infant weight was more highly correlated with height of mother than father. Correlation of infant height and weight at 24 months; mother 0.21, father 0.13
| Weight of 625 children with observations at all intervals (6, 9, 12 and 24 months) Adjusted for maternal height
| Medium |
Daraki et al. (2017), Greece | Cohort study | 772 children | Paternal obesity not associated with child neurodevelopment at 4 years of age | | Medium |
Davey Smith et al. (2007), UK | Cohort study | 4654 children | The association between paternal BMI and offspring BMI at 7.5 years of age:0.202 standardised age and sex adjusted coefficient (0.175–0.229), similar to maternal BMI | Childhood BMI Standardised regression coefficients age and sex adjusted Sensitivity analysis for non-paternity performed Maternal and paternal BMI were included in the same model.
| High |
Durmus et al. (2011), The Netherlands | Cohort study | 5674 children | Pre-pregnancy paternal BMI was strongly associated with childhood overweight at the age of 4 years The main effects of maternal BMI on childhood BMI were stronger than the main effects of paternal BMI (P < 0.001; and P = 0.013, respectively) As compared to children from parents with normal BMI, children from two obese parents had an increased risk of overweight at the age of years, OR 6.52 (3.44–12.38)
| Childhood height, weight and BMI. Maternal BMI had a significantly stronger effect on childhood BMI Adjusted for maternal BMI
| High |
Heppe et al. (2013), The Netherlands | Cohort study | 3610 children | | | High |
Jaaskelainen et al. (2011), Finland | Cohort study (NFBC 1986) | 4788 children | Paternal pre-pregnancy obesity strongly predicted overweight: At 16 years of age: Father–son OR 3.17 (1.70–5.92) Father–daughter OR 5.58 (3.09–10.07) If both parents obese, overweight of the child at 16 years: Sons OR 5.66 (3.12–10.27) Daughters OR 14.84 (7.41–29.73)
| | High |
Lawlor et al. (2007), Australia | Cohort study | 7223 children | The increase in standardized offspring BMI at age 14 for a one SD increase in paternal BMI was 0.239 SD (0.197–0.282) | | Medium |
Lawlor et al. (2008), UK | Cohort study | 4091 children | As assessed at 9 to 11 years of age, mean difference in offspring sex- and age-standardized fat mass z-score per 1 SD BMI 0.24 (0.22–0.26) for maternal BMI versus 0.13 (0.11–0.15) for paternal BMI | Offspring fat and lean mass (measured by dual energy X-ray absorptiometry) Adjusted for maternal BMI Maternal effect size association was larger
| Medium |
Linabery et al. (2013), USA | Cohort study | 912 children | Infants of obese fathers had BMI growth curves distinct from those of normal weight fathers. The p value for the global association between paternal BMI category and infant BMI growth curves (birth-3.5 years) from joint mixed effect model was 0.02 | Infant BMI Maternal BMI has a stronger influence on BMI growth than paternal BMI Missing exposure (11% maternal and 26% paternal BMIs) and covariate data were assumed to be missing at random and imputed, outcomes were not imputed Adjusted for maternal BMI in the joint model
| Medium |
O’Callaghan et al. (1997), Australia | Cohort study | 4062 children | Paternal BMI is independent predictor of severe and moderate obesity at 5 years of age. Paternal BMI percentiles 85–94: Severe obesity RR 2.8 (1.8–4.5) Moderate obesity RR 1.0 (0.6–1.5) Paternal BMI percentiles >95: Severe obesity RR 2.0 (1.1–3.6) Moderate obesity RR 2.1 (1.4–3.3)
| | Medium |
Reilly et al. (2005), UK | Cohort study | 7758 children | Paternal obesity was associated with the risk of obesity in children at 7 years of age. Final model AOR: Father (BMI > 30) 2.54 (1.72–3.75) compared to both parents with BMI < 30. As compared to children from parents with normal BMI, children from two obese parents had an increased risk of overweight at the age of 4 years: OR 6.52 (3.44–12.38)
| | Medium |
Suren et al. (2014), Norway | Cohort study | 92 909 children | ASD in children at the age of 4.0–13.1 (mean 7.4) years: Paternal BMI > 30: versus BMI < 25 AOR 1.73 (1.07–2.82) Asperger disorder in children aged ≥7 years: Paternal BMI > 30 versus BMI < 25 AOR 2.01(1.13–3.57)
| | Medium |
Yeung et al. (2017), USA | Cohort study | 4821 children | Increased risk of failing the personal-social domain in children up to 3 years of age Paternal BMI > 30 compared with children of normal weight fathers AOR 1.71 (1.08–2.70) Children whose parents both had BMI ≥35 were likely to additionally fail the problem-solving domain
| | Medium |
Author, year, country
. | Study design
. | Number of children
. | Results
. | Outcomes
. | Quality
. |
---|
Comments
. |
---|
Adjustments
. |
---|
Original studies n = 14 |
Catalano et al. (2009), USA | Case control study | | Paternal weight at the time birth was greater in children in tertile 3 of weight percentiles compared to children in tertile 1 at follow-up at 8.8 ± 1.8 years No difference in paternal BMI at the time of child’s birth in relation to tertiles of percentage body fat of the child
| Childhood weight and body fat (measured by dual energy X-ray absorptiometry) at follow-up Reference: Centers for Disease Control and Prevention (CDC) weight and body fat percentiles Maternal obstetrical data, paternal anthropometric data and neonatal birth data was included to best determine which combination of perinatal factors best modelled the risk of adiposity in child Maternal pre-pregnancy BMI was the strongest predictor of childhood obesity
| Medium |
Cawley et al. (1954), UK | Cohort study | 1028 children | Infant weight was more highly correlated with height of mother than father. Correlation of infant height and weight at 24 months; mother 0.21, father 0.13
| Weight of 625 children with observations at all intervals (6, 9, 12 and 24 months) Adjusted for maternal height
| Medium |
Daraki et al. (2017), Greece | Cohort study | 772 children | Paternal obesity not associated with child neurodevelopment at 4 years of age | | Medium |
Davey Smith et al. (2007), UK | Cohort study | 4654 children | The association between paternal BMI and offspring BMI at 7.5 years of age:0.202 standardised age and sex adjusted coefficient (0.175–0.229), similar to maternal BMI | Childhood BMI Standardised regression coefficients age and sex adjusted Sensitivity analysis for non-paternity performed Maternal and paternal BMI were included in the same model.
| High |
Durmus et al. (2011), The Netherlands | Cohort study | 5674 children | Pre-pregnancy paternal BMI was strongly associated with childhood overweight at the age of 4 years The main effects of maternal BMI on childhood BMI were stronger than the main effects of paternal BMI (P < 0.001; and P = 0.013, respectively) As compared to children from parents with normal BMI, children from two obese parents had an increased risk of overweight at the age of years, OR 6.52 (3.44–12.38)
| Childhood height, weight and BMI. Maternal BMI had a significantly stronger effect on childhood BMI Adjusted for maternal BMI
| High |
Heppe et al. (2013), The Netherlands | Cohort study | 3610 children | | | High |
Jaaskelainen et al. (2011), Finland | Cohort study (NFBC 1986) | 4788 children | Paternal pre-pregnancy obesity strongly predicted overweight: At 16 years of age: Father–son OR 3.17 (1.70–5.92) Father–daughter OR 5.58 (3.09–10.07) If both parents obese, overweight of the child at 16 years: Sons OR 5.66 (3.12–10.27) Daughters OR 14.84 (7.41–29.73)
| | High |
Lawlor et al. (2007), Australia | Cohort study | 7223 children | The increase in standardized offspring BMI at age 14 for a one SD increase in paternal BMI was 0.239 SD (0.197–0.282) | | Medium |
Lawlor et al. (2008), UK | Cohort study | 4091 children | As assessed at 9 to 11 years of age, mean difference in offspring sex- and age-standardized fat mass z-score per 1 SD BMI 0.24 (0.22–0.26) for maternal BMI versus 0.13 (0.11–0.15) for paternal BMI | Offspring fat and lean mass (measured by dual energy X-ray absorptiometry) Adjusted for maternal BMI Maternal effect size association was larger
| Medium |
Linabery et al. (2013), USA | Cohort study | 912 children | Infants of obese fathers had BMI growth curves distinct from those of normal weight fathers. The p value for the global association between paternal BMI category and infant BMI growth curves (birth-3.5 years) from joint mixed effect model was 0.02 | Infant BMI Maternal BMI has a stronger influence on BMI growth than paternal BMI Missing exposure (11% maternal and 26% paternal BMIs) and covariate data were assumed to be missing at random and imputed, outcomes were not imputed Adjusted for maternal BMI in the joint model
| Medium |
O’Callaghan et al. (1997), Australia | Cohort study | 4062 children | Paternal BMI is independent predictor of severe and moderate obesity at 5 years of age. Paternal BMI percentiles 85–94: Severe obesity RR 2.8 (1.8–4.5) Moderate obesity RR 1.0 (0.6–1.5) Paternal BMI percentiles >95: Severe obesity RR 2.0 (1.1–3.6) Moderate obesity RR 2.1 (1.4–3.3)
| | Medium |
Reilly et al. (2005), UK | Cohort study | 7758 children | Paternal obesity was associated with the risk of obesity in children at 7 years of age. Final model AOR: Father (BMI > 30) 2.54 (1.72–3.75) compared to both parents with BMI < 30. As compared to children from parents with normal BMI, children from two obese parents had an increased risk of overweight at the age of 4 years: OR 6.52 (3.44–12.38)
| | Medium |
Suren et al. (2014), Norway | Cohort study | 92 909 children | ASD in children at the age of 4.0–13.1 (mean 7.4) years: Paternal BMI > 30: versus BMI < 25 AOR 1.73 (1.07–2.82) Asperger disorder in children aged ≥7 years: Paternal BMI > 30 versus BMI < 25 AOR 2.01(1.13–3.57)
| | Medium |
Yeung et al. (2017), USA | Cohort study | 4821 children | Increased risk of failing the personal-social domain in children up to 3 years of age Paternal BMI > 30 compared with children of normal weight fathers AOR 1.71 (1.08–2.70) Children whose parents both had BMI ≥35 were likely to additionally fail the problem-solving domain
| | Medium |
Conclusion: High paternal BMI and weight may be associated with a modest increase in BMI, weight and/or body fat mass in offspring. Low certainty of evidence (GRADE⊕⊕○○).
ASDs and neurodevelopment
Paternal obesity was an independent risk factor for ASD in children in one medium quality study (Suren et al., 2014) (Supplementary Table SII, Table VIII). In the study of Yeung and co-workers (2017) paternal obesity was associated with delays in personal-social functioning, whereas maternal obesity was associated with delays in fine motor development. Daraki and co-workers (2017) did not find any association between paternal obesity and child neurodevelopment at 4 years of age (Supplementary Table SII, Table IV).
Conclusion: It is uncertain whether there is an association between paternal obesity and ASD and neurodevelopment of the child. Very low certainty of evidence (GRADE⊕○○○).
Paternal smoking at childbirth and short-term outcomes for offspring
Obstetric outcomes
Preterm birth
Three cohort studies including more than 30 000 children found no increased risk of PTB (<37 weeks) in children where fathers smoked (Supplementary Table SIII, Table IX). Two of the studies were adjusted for maternal smoking (Horta et al., 1997; Ko et al., 2014) and in one cohort study analyses were performed on non-smoking mothers (Andriani and Kuo, 2014). We included three studies in a meta-analysis and found a slight but not significant effect of paternal smoking on PTB (pooled estimate 1.16, 95% 1.00–1.35) (Fig. 14).
Table IXStudies on the association of paternal smoking with obstetric outcomes and birth defects in offspring
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Quality
. |
---|
Outcomes (Risk estimates)
. | Comment Adjustments
. |
---|
Obstetric outcomes n = 8 |
Andriani and Kuo (2014), Taiwan | Cohort 1993–2007 | | LBW Only father smoking during pregnancy AOR 0.89 (0.51–1.54) 1–10 cig/day AOR 0.81 (0.58–1.14)* 11–20 cig/day AOR 0.66 (0.46–0.94)* ≥20 cig/day AOR 2.09 (1.38–3.17)* PTB Only father smoking during pregnancy AOR 1.16 (0.78–1.71) 1–10 cig/day AOR 0.51 (0.34–0.75)* 11–20 cig/day AOR 0.78 (0.55–1.11)* ≥20 cig/day AOR 2.11 (1.38–3.23)*
| Questionnaires to both parents Adjusted for sex, birth order, maternal age, father’s education, maternal employment status, parental BMI, household income, urban/rural residence *Only adjusted for birth order
| Medium |
Gaizauskiene et al. (2007), Lithuania | | | | Confounders 45 parameters Maternal age < or ≥36 years Education, marriage/cohabiting
| Low |
Horta et al. (1997), Brazil | Cohort 1993 | | LBW: AOR 1.18 (0.94–1.48) PTB: AOR 1.25 (0.99–1.57) IUGR: AOR 1.33 (1.05–1.68)
| Mothers interviewed soon after delivery by trained interviewers Adjusted for social class, maternal schooling, parity, birth interval, prior LBW, maternal height, number of antenatal care visits and for maternal smoking | Medium |
Inoue et al. (2016), Japan | | | LBW Smoking only fathers 502 children with LBW AOR 1.07 (0.94–1.22)
| Birth after GA 37 weeks Mothers interviewed in 1. trimester Adjusted for maternal smoking, paternal smoking (or four types of combination of interaction effect), maternal age, paternal age, maternal BMI, maternal occupational status, parity, sex
| Medium |
Ko et al. (2014), Taiwan | Birth Cohort study 2005–2006
| Total 24 200 children Interview rate 87.8% Included 21 248 children
| | Interview 6 months post-partum (mothers) Adjusted for maternal age, nationality, education, parity, total weight gain during pregnancy, gender of infant, multiple birth and maternal smoking in the same period Similar results for smoking in 1. or 2–3 trimester
| Medium |
Magnus et al. (1984), Norway | | | Birth weight Correlation matrix Paternal smoking Regression coefficients (+/− SE) Bivariate regression −48 (8.9) P < 0.01 Multiple regression −4.9 (9.3) NS
| Paternal height and weight, Maternal height and weight, paternal and maternal education, SES, maternal smoking Correlation matrix
| Low |
Martinez et al. (1994), USA | Cohort study | | | Hospital data at birth + questionnaire ≤1 months after birth by parents Multiple regression analysis for non-smoking Mothers. Adjusted for GA, birth order, ethnicity, maternal and paternal education, maternal age, sex
| Medium |
Zhang and Ratcliffe (1993), Shanghai | | | | Pretested in-hospital interview to mothers after delivery Adjusted for parity, maternal age, gestational age, maternal occupation. Modestly adverse effect on birth weight
| Low |
Birth defects n = 8 |
Cresci et al. (2011), Italy | | | | Questionnaires to both parents. Matched for age range Unconditional regression adjusted for potential confounders but not specified Maternal smoking insignificant but not directly adjusted for
| Low |
Deng et al. (2013), China | | | Non-syndromic CHD Paternal smoking during peri-conception period (3 months before pregnancy and first trimester) and non-smoking mothers No avoidance behaviour: Septal defects: 37 cases/46 controls AOR 2.52 (1.39–4.59) Cono-truncal defects: 36 cases/46 controls AOR 3.22 (1.75–5.93) Other outcomes listed but less than 20 cases
| Maternal face-to-face interview Adjusted for residence, age, education, pre-pregnant BMI, alcohol use, folic acid use, paternal alcohol and family history of CHD | Low |
Figueiredo et al. (2015), USA | | 430 cases 754 controls Fathers smoking 173 cases 245 controls
| | Interview of mothers Age <3 years Adjusted for sex, parental employment and education and age, location at birth rural/city, country Maternal smoking infrequent - only 1.4–1.9%
| Medium |
Krapels et al. (2006), The Netherlands | Case control | | Orofacial cleft Univariate analyses paternal smoking: >10 cigarettes per day: Cleft lip with or without cleft palate: OR 1.5 (1.0–2.4) Cleft palate only: OR 1.8 (0.9–3.5)
| Questionnaires to both parents Follow-up two years after the peri-conception period Multivariate analyses are not shown for paternal smoking but was not significant
| Low |
Kuciene and Dulskiene (2010), Lithuania | | | | Interviews of both parents, mostly mothersAdjusted for maternal education, social status, and marital status | Low |
Savitz et al. (1991), USA | Cohort study of singleton live births 1959–1966 | | Congenital anomalies Paternal smoking Cleft lip with or without cleft palate: POR 1.7 (0.5–6.0) Hydrocephalus: POR 2.4 (0.6–9.3) Ventricular septal defect: POR 2.0 (0.9–4.3) Urethral stenosis: POR 2.0 (0.6–6.4)
| Interview by mothers at first prenatal care visit Adjusted for maternal age, race, education and maternal smoking
| Medium |
van Rooij et al. (2010), The Netherlands | | | | | Low |
Wasserman et al. (1996), USA | | | Birth defects Father only smokers: Cono-truncal heart: 35/90 OR 0.93 (0.58–1.5) Neural tube: 59/90 OR 1.1 (0.76–1.7) Limb reduction defect: 41/90 OR 1.4 (0.88–2.2)
| Telephone interview of mothers Paternal smoking 1 month before through 3 months after conception. Risk estimates were adjusted for selected non-specified covariates did not differ substantially from crude estimates.
| Low |
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Quality
. |
---|
Outcomes (Risk estimates)
. | Comment Adjustments
. |
---|
Obstetric outcomes n = 8 |
Andriani and Kuo (2014), Taiwan | Cohort 1993–2007 | | LBW Only father smoking during pregnancy AOR 0.89 (0.51–1.54) 1–10 cig/day AOR 0.81 (0.58–1.14)* 11–20 cig/day AOR 0.66 (0.46–0.94)* ≥20 cig/day AOR 2.09 (1.38–3.17)* PTB Only father smoking during pregnancy AOR 1.16 (0.78–1.71) 1–10 cig/day AOR 0.51 (0.34–0.75)* 11–20 cig/day AOR 0.78 (0.55–1.11)* ≥20 cig/day AOR 2.11 (1.38–3.23)*
| Questionnaires to both parents Adjusted for sex, birth order, maternal age, father’s education, maternal employment status, parental BMI, household income, urban/rural residence *Only adjusted for birth order
| Medium |
Gaizauskiene et al. (2007), Lithuania | | | | Confounders 45 parameters Maternal age < or ≥36 years Education, marriage/cohabiting
| Low |
Horta et al. (1997), Brazil | Cohort 1993 | | LBW: AOR 1.18 (0.94–1.48) PTB: AOR 1.25 (0.99–1.57) IUGR: AOR 1.33 (1.05–1.68)
| Mothers interviewed soon after delivery by trained interviewers Adjusted for social class, maternal schooling, parity, birth interval, prior LBW, maternal height, number of antenatal care visits and for maternal smoking | Medium |
Inoue et al. (2016), Japan | | | LBW Smoking only fathers 502 children with LBW AOR 1.07 (0.94–1.22)
| Birth after GA 37 weeks Mothers interviewed in 1. trimester Adjusted for maternal smoking, paternal smoking (or four types of combination of interaction effect), maternal age, paternal age, maternal BMI, maternal occupational status, parity, sex
| Medium |
Ko et al. (2014), Taiwan | Birth Cohort study 2005–2006
| Total 24 200 children Interview rate 87.8% Included 21 248 children
| | Interview 6 months post-partum (mothers) Adjusted for maternal age, nationality, education, parity, total weight gain during pregnancy, gender of infant, multiple birth and maternal smoking in the same period Similar results for smoking in 1. or 2–3 trimester
| Medium |
Magnus et al. (1984), Norway | | | Birth weight Correlation matrix Paternal smoking Regression coefficients (+/− SE) Bivariate regression −48 (8.9) P < 0.01 Multiple regression −4.9 (9.3) NS
| Paternal height and weight, Maternal height and weight, paternal and maternal education, SES, maternal smoking Correlation matrix
| Low |
Martinez et al. (1994), USA | Cohort study | | | Hospital data at birth + questionnaire ≤1 months after birth by parents Multiple regression analysis for non-smoking Mothers. Adjusted for GA, birth order, ethnicity, maternal and paternal education, maternal age, sex
| Medium |
Zhang and Ratcliffe (1993), Shanghai | | | | Pretested in-hospital interview to mothers after delivery Adjusted for parity, maternal age, gestational age, maternal occupation. Modestly adverse effect on birth weight
| Low |
Birth defects n = 8 |
Cresci et al. (2011), Italy | | | | Questionnaires to both parents. Matched for age range Unconditional regression adjusted for potential confounders but not specified Maternal smoking insignificant but not directly adjusted for
| Low |
Deng et al. (2013), China | | | Non-syndromic CHD Paternal smoking during peri-conception period (3 months before pregnancy and first trimester) and non-smoking mothers No avoidance behaviour: Septal defects: 37 cases/46 controls AOR 2.52 (1.39–4.59) Cono-truncal defects: 36 cases/46 controls AOR 3.22 (1.75–5.93) Other outcomes listed but less than 20 cases
| Maternal face-to-face interview Adjusted for residence, age, education, pre-pregnant BMI, alcohol use, folic acid use, paternal alcohol and family history of CHD | Low |
Figueiredo et al. (2015), USA | | 430 cases 754 controls Fathers smoking 173 cases 245 controls
| | Interview of mothers Age <3 years Adjusted for sex, parental employment and education and age, location at birth rural/city, country Maternal smoking infrequent - only 1.4–1.9%
| Medium |
Krapels et al. (2006), The Netherlands | Case control | | Orofacial cleft Univariate analyses paternal smoking: >10 cigarettes per day: Cleft lip with or without cleft palate: OR 1.5 (1.0–2.4) Cleft palate only: OR 1.8 (0.9–3.5)
| Questionnaires to both parents Follow-up two years after the peri-conception period Multivariate analyses are not shown for paternal smoking but was not significant
| Low |
Kuciene and Dulskiene (2010), Lithuania | | | | Interviews of both parents, mostly mothersAdjusted for maternal education, social status, and marital status | Low |
Savitz et al. (1991), USA | Cohort study of singleton live births 1959–1966 | | Congenital anomalies Paternal smoking Cleft lip with or without cleft palate: POR 1.7 (0.5–6.0) Hydrocephalus: POR 2.4 (0.6–9.3) Ventricular septal defect: POR 2.0 (0.9–4.3) Urethral stenosis: POR 2.0 (0.6–6.4)
| Interview by mothers at first prenatal care visit Adjusted for maternal age, race, education and maternal smoking
| Medium |
van Rooij et al. (2010), The Netherlands | | | | | Low |
Wasserman et al. (1996), USA | | | Birth defects Father only smokers: Cono-truncal heart: 35/90 OR 0.93 (0.58–1.5) Neural tube: 59/90 OR 1.1 (0.76–1.7) Limb reduction defect: 41/90 OR 1.4 (0.88–2.2)
| Telephone interview of mothers Paternal smoking 1 month before through 3 months after conception. Risk estimates were adjusted for selected non-specified covariates did not differ substantially from crude estimates.
| Low |
Table IXStudies on the association of paternal smoking with obstetric outcomes and birth defects in offspring
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Quality
. |
---|
Outcomes (Risk estimates)
. | Comment Adjustments
. |
---|
Obstetric outcomes n = 8 |
Andriani and Kuo (2014), Taiwan | Cohort 1993–2007 | | LBW Only father smoking during pregnancy AOR 0.89 (0.51–1.54) 1–10 cig/day AOR 0.81 (0.58–1.14)* 11–20 cig/day AOR 0.66 (0.46–0.94)* ≥20 cig/day AOR 2.09 (1.38–3.17)* PTB Only father smoking during pregnancy AOR 1.16 (0.78–1.71) 1–10 cig/day AOR 0.51 (0.34–0.75)* 11–20 cig/day AOR 0.78 (0.55–1.11)* ≥20 cig/day AOR 2.11 (1.38–3.23)*
| Questionnaires to both parents Adjusted for sex, birth order, maternal age, father’s education, maternal employment status, parental BMI, household income, urban/rural residence *Only adjusted for birth order
| Medium |
Gaizauskiene et al. (2007), Lithuania | | | | Confounders 45 parameters Maternal age < or ≥36 years Education, marriage/cohabiting
| Low |
Horta et al. (1997), Brazil | Cohort 1993 | | LBW: AOR 1.18 (0.94–1.48) PTB: AOR 1.25 (0.99–1.57) IUGR: AOR 1.33 (1.05–1.68)
| Mothers interviewed soon after delivery by trained interviewers Adjusted for social class, maternal schooling, parity, birth interval, prior LBW, maternal height, number of antenatal care visits and for maternal smoking | Medium |
Inoue et al. (2016), Japan | | | LBW Smoking only fathers 502 children with LBW AOR 1.07 (0.94–1.22)
| Birth after GA 37 weeks Mothers interviewed in 1. trimester Adjusted for maternal smoking, paternal smoking (or four types of combination of interaction effect), maternal age, paternal age, maternal BMI, maternal occupational status, parity, sex
| Medium |
Ko et al. (2014), Taiwan | Birth Cohort study 2005–2006
| Total 24 200 children Interview rate 87.8% Included 21 248 children
| | Interview 6 months post-partum (mothers) Adjusted for maternal age, nationality, education, parity, total weight gain during pregnancy, gender of infant, multiple birth and maternal smoking in the same period Similar results for smoking in 1. or 2–3 trimester
| Medium |
Magnus et al. (1984), Norway | | | Birth weight Correlation matrix Paternal smoking Regression coefficients (+/− SE) Bivariate regression −48 (8.9) P < 0.01 Multiple regression −4.9 (9.3) NS
| Paternal height and weight, Maternal height and weight, paternal and maternal education, SES, maternal smoking Correlation matrix
| Low |
Martinez et al. (1994), USA | Cohort study | | | Hospital data at birth + questionnaire ≤1 months after birth by parents Multiple regression analysis for non-smoking Mothers. Adjusted for GA, birth order, ethnicity, maternal and paternal education, maternal age, sex
| Medium |
Zhang and Ratcliffe (1993), Shanghai | | | | Pretested in-hospital interview to mothers after delivery Adjusted for parity, maternal age, gestational age, maternal occupation. Modestly adverse effect on birth weight
| Low |
Birth defects n = 8 |
Cresci et al. (2011), Italy | | | | Questionnaires to both parents. Matched for age range Unconditional regression adjusted for potential confounders but not specified Maternal smoking insignificant but not directly adjusted for
| Low |
Deng et al. (2013), China | | | Non-syndromic CHD Paternal smoking during peri-conception period (3 months before pregnancy and first trimester) and non-smoking mothers No avoidance behaviour: Septal defects: 37 cases/46 controls AOR 2.52 (1.39–4.59) Cono-truncal defects: 36 cases/46 controls AOR 3.22 (1.75–5.93) Other outcomes listed but less than 20 cases
| Maternal face-to-face interview Adjusted for residence, age, education, pre-pregnant BMI, alcohol use, folic acid use, paternal alcohol and family history of CHD | Low |
Figueiredo et al. (2015), USA | | 430 cases 754 controls Fathers smoking 173 cases 245 controls
| | Interview of mothers Age <3 years Adjusted for sex, parental employment and education and age, location at birth rural/city, country Maternal smoking infrequent - only 1.4–1.9%
| Medium |
Krapels et al. (2006), The Netherlands | Case control | | Orofacial cleft Univariate analyses paternal smoking: >10 cigarettes per day: Cleft lip with or without cleft palate: OR 1.5 (1.0–2.4) Cleft palate only: OR 1.8 (0.9–3.5)
| Questionnaires to both parents Follow-up two years after the peri-conception period Multivariate analyses are not shown for paternal smoking but was not significant
| Low |
Kuciene and Dulskiene (2010), Lithuania | | | | Interviews of both parents, mostly mothersAdjusted for maternal education, social status, and marital status | Low |
Savitz et al. (1991), USA | Cohort study of singleton live births 1959–1966 | | Congenital anomalies Paternal smoking Cleft lip with or without cleft palate: POR 1.7 (0.5–6.0) Hydrocephalus: POR 2.4 (0.6–9.3) Ventricular septal defect: POR 2.0 (0.9–4.3) Urethral stenosis: POR 2.0 (0.6–6.4)
| Interview by mothers at first prenatal care visit Adjusted for maternal age, race, education and maternal smoking
| Medium |
van Rooij et al. (2010), The Netherlands | | | | | Low |
Wasserman et al. (1996), USA | | | Birth defects Father only smokers: Cono-truncal heart: 35/90 OR 0.93 (0.58–1.5) Neural tube: 59/90 OR 1.1 (0.76–1.7) Limb reduction defect: 41/90 OR 1.4 (0.88–2.2)
| Telephone interview of mothers Paternal smoking 1 month before through 3 months after conception. Risk estimates were adjusted for selected non-specified covariates did not differ substantially from crude estimates.
| Low |
Author, year, country
. | Study design
. | Number of deliveries or children
. | Result
. | Quality
. |
---|
Outcomes (Risk estimates)
. | Comment Adjustments
. |
---|
Obstetric outcomes n = 8 |
Andriani and Kuo (2014), Taiwan | Cohort 1993–2007 | | LBW Only father smoking during pregnancy AOR 0.89 (0.51–1.54) 1–10 cig/day AOR 0.81 (0.58–1.14)* 11–20 cig/day AOR 0.66 (0.46–0.94)* ≥20 cig/day AOR 2.09 (1.38–3.17)* PTB Only father smoking during pregnancy AOR 1.16 (0.78–1.71) 1–10 cig/day AOR 0.51 (0.34–0.75)* 11–20 cig/day AOR 0.78 (0.55–1.11)* ≥20 cig/day AOR 2.11 (1.38–3.23)*
| Questionnaires to both parents Adjusted for sex, birth order, maternal age, father’s education, maternal employment status, parental BMI, household income, urban/rural residence *Only adjusted for birth order
| Medium |
Gaizauskiene et al. (2007), Lithuania | | | | Confounders 45 parameters Maternal age < or ≥36 years Education, marriage/cohabiting
| Low |
Horta et al. (1997), Brazil | Cohort 1993 | | LBW: AOR 1.18 (0.94–1.48) PTB: AOR 1.25 (0.99–1.57) IUGR: AOR 1.33 (1.05–1.68)
| Mothers interviewed soon after delivery by trained interviewers Adjusted for social class, maternal schooling, parity, birth interval, prior LBW, maternal height, number of antenatal care visits and for maternal smoking | Medium |
Inoue et al. (2016), Japan | | | LBW Smoking only fathers 502 children with LBW AOR 1.07 (0.94–1.22)
| Birth after GA 37 weeks Mothers interviewed in 1. trimester Adjusted for maternal smoking, paternal smoking (or four types of combination of interaction effect), maternal age, paternal age, maternal BMI, maternal occupational status, parity, sex
| Medium |
Ko et al. (2014), Taiwan | Birth Cohort study 2005–2006
| Total 24 200 children Interview rate 87.8% Included 21 248 children
| | Interview 6 months post-partum (mothers) Adjusted for maternal age, nationality, education, parity, total weight gain during pregnancy, gender of infant, multiple birth and maternal smoking in the same period Similar results for smoking in 1. or 2–3 trimester
| Medium |
Magnus et al. (1984), Norway | | | Birth weight Correlation matrix Paternal smoking Regression coefficients (+/− SE) Bivariate regression −48 (8.9) P < 0.01 Multiple regression −4.9 (9.3) NS
| Paternal height and weight, Maternal height and weight, paternal and maternal education, SES, maternal smoking Correlation matrix
| Low |
Martinez et al. (1994), USA | Cohort study | | | Hospital data at birth + questionnaire ≤1 months after birth by parents Multiple regression analysis for non-smoking Mothers. Adjusted for GA, birth order, ethnicity, maternal and paternal education, maternal age, sex
| Medium |
Zhang and Ratcliffe (1993), Shanghai | | | | Pretested in-hospital interview to mothers after delivery Adjusted for parity, maternal age, gestational age, maternal occupation. Modestly adverse effect on birth weight
| Low |
Birth defects n = 8 |
Cresci et al. (2011), Italy | | | | Questionnaires to both parents. Matched for age range Unconditional regression adjusted for potential confounders but not specified Maternal smoking insignificant but not directly adjusted for
| Low |
Deng et al. (2013), China | | | Non-syndromic CHD Paternal smoking during peri-conception period (3 months before pregnancy and first trimester) and non-smoking mothers No avoidance behaviour: Septal defects: 37 cases/46 controls AOR 2.52 (1.39–4.59) Cono-truncal defects: 36 cases/46 controls AOR 3.22 (1.75–5.93) Other outcomes listed but less than 20 cases
| Maternal face-to-face interview Adjusted for residence, age, education, pre-pregnant BMI, alcohol use, folic acid use, paternal alcohol and family history of CHD | Low |
Figueiredo et al. (2015), USA | | 430 cases 754 controls Fathers smoking 173 cases 245 controls
| | Interview of mothers Age <3 years Adjusted for sex, parental employment and education and age, location at birth rural/city, country Maternal smoking infrequent - only 1.4–1.9%
| Medium |
Krapels et al. (2006), The Netherlands | Case control | | Orofacial cleft Univariate analyses paternal smoking: >10 cigarettes per day: Cleft lip with or without cleft palate: OR 1.5 (1.0–2.4) Cleft palate only: OR 1.8 (0.9–3.5)
| Questionnaires to both parents Follow-up two years after the peri-conception period Multivariate analyses are not shown for paternal smoking but was not significant
| Low |
Kuciene and Dulskiene (2010), Lithuania | | | | Interviews of both parents, mostly mothersAdjusted for maternal education, social status, and marital status | Low |
Savitz et al. (1991), USA | Cohort study of singleton live births 1959–1966 | | Congenital anomalies Paternal smoking Cleft lip with or without cleft palate: POR 1.7 (0.5–6.0) Hydrocephalus: POR 2.4 (0.6–9.3) Ventricular septal defect: POR 2.0 (0.9–4.3) Urethral stenosis: POR 2.0 (0.6–6.4)
| Interview by mothers at first prenatal care visit Adjusted for maternal age, race, education and maternal smoking
| Medium |
van Rooij et al. (2010), The Netherlands | | | | | Low |
Wasserman et al. (1996), USA | | | Birth defects Father only smokers: Cono-truncal heart: 35/90 OR 0.93 (0.58–1.5) Neural tube: 59/90 OR 1.1 (0.76–1.7) Limb reduction defect: 41/90 OR 1.4 (0.88–2.2)
| Telephone interview of mothers Paternal smoking 1 month before through 3 months after conception. Risk estimates were adjusted for selected non-specified covariates did not differ substantially from crude estimates.
| Low |
Figure 14
Forest plot describing the association between paternal smoking and risk for PTB.
Conclusion: There may be little or no association between paternal smoking and PTB. Low certainty of evidence (GRADE⊕⊕○○).
Low BW
Seven studies (six cohort and one case control), comprising more than 60 000 children, investigated the association between paternal smoking during preconception/pregnancy and BW (Supplementary Table SIII, Table IX). In four cohort studies, all adjusted for maternal smoking, no increased risk of LBW was observed in pregnancies where fathers smoked (Horta et al., 1997; Andriani and Kuo, 2014; Ko et al., 2014; Inoue et al., 2016).
Two cohort studies (Magnus et al., 1984; Martinez et al., 1994) and one case control study (Zhang and Ratcliffe, 1993) explored the association between BW and paternal smoking. Martinez et al. (1994) showed that the number of cigarettes smoked by the father was associated with lower BW in children with non-smoking mothers (test for linearity P < 0.03). This was in line with Zhang, where paternal smoking had a modest effect on BW, the mean BW being 30 grams lower in pregnancies where the fathers smoked (Zhang and Ratcliffe, 1993). In the study by Magnus, paternal smoking had no independent effect on BW in the offspring (Magnus et al., 1984). We performed a meta-analysis including four studies. A small but not significant effect of paternal smoking on the incidence of LBW was found (pooled estimate 1.10, 95% 1.00–1.21) (Fig. 15).
Figure 15
Forest plot describing the association between paternal smoking and risk for LBW in offspring.
Conclusion: There appears to be little or no association between paternal smoking and LBW. Low certainty of evidence (GRADE⊕⊕○○).
SGA/intrauterine growth retardation
Two cohort studies investigated SGA/ IUGR, defined as BW <10th percentile for gestational age and sex (Horta et al., 1997; Ko et al., 2014), comprising more than 27 000 children in total (Supplementary Table SIII, Table IX). In Horta et al. (1997) the adjusted risk of SGA/IUGR was significantly increased in pregnancies with paternal smoking, AOR 1.33 (95% CI 1.05–1.68), while in the study by Ko et al. (2014) no significant association was found (AOR 1.12 (95% CI 0.90–1.40) for SGA/IUGR. Figures were similar for paternal smoking in the first, second and third trimesters (Ko et al., 2014). A meta-analysis including two studies showed a pooled estimate of 1.21 (95% CI 1.03–1.44) (Fig. 16).
Figure 16
Forest plot describing the association between paternal smoking and risk for SGA in offspring.
Conclusion: Paternal smoking may be associated with a small increase in SGA/IUGR. Low certainty of evidence (GRADE⊕⊕○○).
Perinatal mortality
One cohort study of medium quality from Lithuania (comprising 29 619 births) including 296 perinatal deaths found an increased risk of perinatal death when fathers smoked (AOR 1.72, 95% CI was not available) (Gaizauskiene et al., 2007) (Supplementary Table SIII, Table IX). The probability of foetal and NND was 0.009 in the offspring of fathers who smoked, in comparison with 0.005 in the offspring of non-smoking parents.
Conclusion: It is uncertain whether paternal smoking is associated with perinatal death. Very low certainty of evidence (GRADE⊕○○○).
Birth defects
Eight studies (one cohort and seven case control) reported birth defects in relation to paternal smoking before and during pregnancy (Supplementary Table SIII, Table IX). The cohort study included 14 685 births for analysis and found no significant association between paternal smoking and children with orofacial clefts, hydrocephalus, ventricular septal defect (VSD) and urethral stenosis (Savitz et al., 1991). There were seven case control studies. These included a total of 1977 cases, where four studies reported CHD (n = 1112) (Wasserman et al., 1996; Kuciene and Dulskiene, 2010; Cresci et al., 2011; Deng et al., 2013), two studies reported orofacial clefts (n = 780) (Krapels et al., 2006; Figueiredo et al., 2015) and one study reported anorectal defects (n = 85 cases) (van Rooij et al., 2010). Wasserman et al. (1996) also reported neural tube defects (n = 264 cases) and limb reduction defects (n = 178 cases).
The three CHD studies showed a significantly increased risk associated with paternal smoking with AOR ranging from 1.45 to 3.2 (Kuciene and Dulskiene, 2010; Cresci et al., 2011; Deng et al., 2013), while Wasserman et al. (1996) showed no association (AOR 0.93, 95% CI 0.58–1.5). Savitz et al. (1991) found no significant association of paternal smoking and VSD (AOR 2.0, 95% CI 0.9–4.3).
We included six studies in a meta-analysis and found a positive association between paternal smoking and CHD (pooled estimate 1.75 (95% CI 1.25–2.44) (Fig. 17).
Figure 17
Forest plot describing the association between paternal smoking and risk for CHDs in offspring.
There was also a positive association between paternal smoking and orofacial clefts in both case control studies (AOR from 1.45 to 1.5) (Krapels et al., 2006; Figueiredo et al., 2015). However, there was no significantly increased risk in the cohort study, with an APOR 1.7 (95% CI 0.5–6.0) (Savitz et al., 1991). Furthermore, there was a significant association between paternal smoking and anorectal malformations (AOR 1.8, 95% CI 1.1–2.9) (van Rooij et al., 2010). Our meta-analysis, including two studies of paternal smoking and orofacial clefts, showed a positive association, with a pooled estimate of 1.51 (95% CI 1.16–1.97) (Fig. 18). However, none of the other birth defects we explored showed a significant association with paternal smoking.
Figure 18
Forest plot describing the association between paternal smoking and risk for orofacial clefts.
Conclusion: Paternal smoking may be associated with a modest increase in CHD and orofacial clefts. Low certainty of evidence (GRADE⊕⊕○○).
Paternal smoking at childbirth and long-term outcomes for offspring
Cancer
Five studies explored the association between paternal smoking during pregnancy and cancers in offspring (Supplementary Table SIII, Table X). Of these, three studies divided smoking into two sharply distinguished classifications, smoking/non-smoking, but only reported dose-response estimates (Ji et al., 1997; Sorahan et al., 2001; Pang et al., 2003). In the use of cigarettes >5 pack-years, Ji et al. (1997) found a significant association between paternal smoking and cancer in offspring (AOR 1.7, 95% CI 1.2–2.5). Likewise Sorahan et al. (2001) showed a significant association between smoking and cancer: 10 to 19 cigarettes per day (AOR 1.63, 95% CI 1.10–2.41) and 20–29 cigarettes per day (AOR 1.46, (95% CI 1.05–2.03). However, Pang et al. (2003) did not show an association between cancer and the father smoking >20 cigarettes per day. In the two studies with the smoking/non-smoking dichotomy, Sorahan and Lancashire (2004) showed a significant association between smoking and cancer in offspring (AOR 1.28, 95% CI 1.15–1.42), while John et al. (1991) did not. Childhood acute leukaemia and brain tumours are dealt with in the sections below, while paternal smoking was not associated with any of the specific cancers in any of the studies.
Table XStudies on the association of paternal smoking with long-term outcomes in offspring.
Author, year, country
. | Study design
. | Number of deliveries and children
. | Result
. | Outcomes Adjustments
. | Quality assessment
. |
---|
Outcomes (Risk estimates)
. |
---|
Cancer |
Acute childhood leukaemia Meta-analyses n = 3 |
Metayer et al. (2016), USA | | Childhood Leukaemia International Consortium (CLIC) studies: Meta-analyses including 6–9 CLIC studies and 3–4 Non-CLIC studies Pooled analysis of 12 case control studies with 1330 AML 13 169 controls
| AML Paternal smoking during preconception period MA (CLIC+non-CLIC): AOR 1.19 (1.00–1.41) Pooled CLIC studies: AOR 1.18 (1.01–1.38)* Paternal smoking during pregnancy MA (CLIC+non-CLIC): AOR 1.28 (1.05–1.57) Pooled CLIC studies: AOR 1.24 (1.06–1.46)* Paternal ever smoking MA (CLIC+non-CLCI): AOR 1.18 (0.92–1.51) Pooled CLIC studies: AOR1.34 (1.11–1.62)*
| Interview with mothers and/or fathers, age <15 yrs Adjusted for age, sex, ethnicity, paternal education, study centre *Similar results for analyses including only non-smoking mothers (data not shown) Dose-response relationship with paternal smoking Maternal smoking had no effect in pooled CLIC analysis or meta-analysis and is not adjusted for High correlation between pre-and postnatal paternal smoking. Limited ability to identify specific windows of exposure
| Medium |
Milne et al. (2012), Australia | | | ALL Paternal smoking around the time of conception: Any versus none: OR 1.15 (1.06–1.24) >20 CPD: OR 1.44 (1.24–1.68)
| | Low |
Liu et al. (2011), USA | SR and meta-analysis, 18 case control studies
| Preconception: 13 studies Cases and controls: NA
| ALL Paternal smoking during preconception: AOR 1.25 (1.08–1.46)* Paternal smoking during pregnancy: AOR 1.24 (1.07–1.43) Dose-response a. >10 CPD; b. 10–19; c.>20 a. AOR 1.17 (0.9–1.54) b. AOR 1.25 (1.01–1.55) c. AOR 1.30 (1.09–1.55)
| Primarily interviews by mothers Age 18 month to 18 years Most studies matched and adjusted for potential confounders *Only 5 studies included in MA adjusted for maternal smoking Also, a positive association between ALL and paternal ever smoking and at each exposure time period examined
| Medium |
Original articles n = 19 |
Brondum et al. (1999), USA | Case control (CCG study) 1989–93
| 1618 ALL 1722 controls 450 AML 523 controls
| ALL Paternal smoking 1 month before pregnancy AOR 1.07 (0.90–1.27) Father (not mother) ever smoked (n = 1842) AOR 1.04 (0.86–1.26) AML Paternal smoking 1 month before pregnancy AOR 0.87 (0.64–1.18) Father (not mother) ever smoked (n = 517) AOR 1.32 (0.91–1.93)
| Telephone interview with parents mostly mothers Child age: ALL <15 years, AML <18 years Matched by age, race, telephone code area Adjusted for annual income, father’s and mother’s exposures, race and education No association with maternal smoking, parental years of smoking, or number of pack-years
| Medium |
Castro-Jimenez and Orozco-Vargas (2011), Colombia | | | | Face-to-face interview with parents Age <15 years Matched control sex, age, region Not adjusted for maternal smoking but of no significance
| Low |
Chang et al. (2006), USA | | | | Self-administered questionnaire/in-person interview of mothers Age <15 years Matched on age, maternal race, and Hispanic ethnicity. Adjusting for household income Maternal smoking was not associated with increased risk of ALL or AML Data included in Metayer et al. (2013)
| Low |
Farioli et al. (2014), Italy | Case control 1998–2003 (SETIL study)
| 557 cases 855 controls 1–10 CPD: 77 cases 108 controls >10 CPD: 151 cases 222 controls
| | Personal interview with parents Age <10 years Mutually adjusted models also including paternal smoking during pregnancy and maternal smoking in first trimester Child second-hand-smoking (SHS), birth order, BW, duration of breast feeding, mat and pat age, educational level, birth year mother, parental exposure benzene
| Low |
Ji et al. (1997), China | | 642 cases 642 controls No maternal smoking Acute leukaemia 166 case control pairs Lymphoma 87 case control pairs
| Cancer <2 Pack-years (PY) 2–5 PY >5 PY prior to conception Acute leukaemia AOR 2.4 (1.1–5.6)* ALL AOR 3.8 (1.3–12.3)* AML AOR 2.3 (0.4–14.8)* Lymphoma AOR 4.5 (1.2–16.8)* All cancers AOR 1.7 (1.2–2.5)*
| Paternal and maternal interviews by trained interviewers Age <15 years. Matched for sex, year of birth Adjusted for BW, income, paternal age, education and alcohol For <5 PY there were no significant risk in any of the cancers
| Low |
John et al. (1991), USA | | | Cancer Paternal smoking preconception period, absence of maternal smoking ALL: AOR 1.4 (0.6–3.1) Lymphomas: AOR 1.6 (0.5–5.4) Brain cancer: 1.6 (0.7–3.5) All cancers: AOR 1.2 (0.8–2.1)
| Personal interview Prenatal exposure Age 0–14 years Matched for age, sex, area Absence of maternal smoking: Adjusted for father’s education.
| Low |
Lee et al. (2009), Chorea | | 164 cases leukaemia 106 ALL 164 controls
| | Interview with mothers (93.5%) Age 0–18 years Matched for age and sex. Adjusted for age, gender, father’s education and birth weight Maternal smoking was too small (6.1% in controls) to be evaluated in childhood leukaemia risk and was not considered further
| Low |
MacArthur et al. (2008), Canada | | 399 cases 399 controls 109 cases 96 controls
| Acute leukaemiaAOR 0.99 (0.50–1.99) AOR 1.18 (0.70–1.20) AOR 1.14 (0.79–1.64)
APR 0.87 (0.42–1.81) AOR 1.21 (0.70–2.08) AOR 1.15 (0.79–1.67)
AOR 2.98 (0.70–12.75) AOR 0.93 (0.25–3.45) AOR 0.90 (0.34–2.38)
| Personal interviews with each child parents Age 0–14 years Matched for age, gender, area Conditional logistic regression Maternal age, mat education, household income, ethnicity, and no of residences since birth Not directly adjusted maternal Smoking, but maternal risk estimates did not change when paternal smoking patterns were considered
| Low |
Magnani et al. (1990) | Case control 1974–1980 1981–1984
| 142 ALL 22 AnLL 19 (NHL) 307 controls
| | | Low |
Mattioli et al. (2014), Italy | Case control (SETIL study) 1998–2003
| | Acute non-Lymphatic Leukaemia (AnLL) Paternal smoking in the conception period 1–10 CPD: AOR 1.34 (0.65–2.76) ≥11 CPD: AOR 1.79 (1.01–3.15)
| Personal interview of parents Age 0–10 years Matched for date of birth, sex, residence Inverse probability weighting adjusting for sex, provenience, birth order, BW, breast feeding, parental educational level, age, birth year, occupational exposure to benzene Not directly adjusted maternal smoking but no association on AnLL and maternal smoking during pregnancy
| Low |
Menegaux et al. (2007), France | Case control 1995–1998 | 472 cases 407 ALL 62 AML 3 other 567 controls
| Childhood acute leukaemia (ALL and AML) Paternal smoking 3 months before pregnancy All acute leukaemia ≤20 CPD: AOR 1.2 (0.9–1.6) >20CPD: AOR 1.0 (0.6–1.7) ALL ≤20 CPD: AOR 1.2 (0.9–1.6) >20 CPD: AOR 1.2 (0.7–2.0) AML ≤20 CPD: AOR 0.9 (0.5–1.7) >20 CPD: AOR 0.2 (0.02–1.7)
| Standardised self- administered questionnaire to mothers Age <15 years Matched for age, gender, region Adjusted for matched age, gender, region, socio-professional category, birth order Not directly adjusted for maternal smoking but not significant
| Low |
Metayer et al. (2013), USA | Case control (NCCLS study) 1996–2008
| 767 ALL 135 AML 1139 controls
| ALL and AML Paternal prenatal smoking (3 month before and/or during pregnancy) ALL: AOR 1.17 (0.91–1.50)* AML: AOR 1.36 (0.82–2.24)* Paternal prenatal smoking and child’s passive smoking ALL: AOR 0.94 (0.69–1.27)** AML: AOR 1.14 (0.55–2.39)**
| Phase 1: Self-administered questionnaire/ Phase 2: In-person interview of mainly mothers Age < 15 years Matched on age, maternal race, and Hispanic ethnicity Adjusting for matching variables and household income *Not adjusted for maternal smoking but no significant association with ALL or AML **adjusted for maternal prenatal smoking Expansion of Chang et al. (2006)
| Low |
Milne et al. (2012), Australia | Case control (Aus-ALL study) 2003–2006
| | ALL Paternal smoking during conception year: Any: AOR 1.22 (0.92–1.61) 1–14 CPD: AOR 1.00 (0.66–1.52) >15 CPD: AOR 1.35 (0.98–1.86)
| Self-administered questionnaires from both parents Age <15 years Matched by age, sex, state of residence Adjusted for matching variables, paternal age, parental education, ethnicity Maternal smoking was not associated with ALL and paternal smoking unchanged when adjusted for maternal smoking (data not shown)
| Low |
Orsi et al. (2015), France | | 747 CL 636 ALL 100 AML 1421 controls
| All leukaemia (AL), ALL, AML Paternal preconception smoking: AL: AOR 1.3 (1.0–1.6) ALL: AOR 1.2 (0.9–1.6) AML: AOR 1.6 (1.0–2.8) Paternal smoking during pregnancy: AL: AOR 1.3 (1.1–1.6) ALL: AOR 1.3 (1.0–1.6) AML: AOR 1.6 (1.0–2.5)
| Telephone interview with parents, mostly mothers Age <15 years Matched for age, sex Adjusted for age, sex, mother’s age and education, birth order and maternal smoking
| Low |
Pang et al. (2003), UK | Case control (UKCCS) 1991–96
| 3585 case fathers 6987 control fathers
| Leukaemia Paternal preconception smoking 1–19 CPD: AOR 1.12 (0.96–1.32) 20+ CPD: AOR 1.01 (0.87–1.17) ALL: AOR 1.04 (0.91–1.18) AML: AOR 1.07 (0.80–1.43)
| Personal interview with parents Age <15 years Matched for sex, age, region Adjusted for matching variables, parental age, deprivation score
| Medium |
Rudant et al. (2008), France | Case control (ESCALE study) 2003–4
| 647 ALL 102 AML 1681 controls 128 HL 848 controls 164 NHL 1312 controls
| Hematopoietic malignancies Paternal smoking from the year prior to the child’s birth to the interview ALL: AOR 1.4 (1.1–1.7) AML: AOR 1.5 (1.0–2.3) Hodgkin’s lymphoma (HL): AOR 1.2 (0.8–1.7) Non-Hodgkin’s lymphoma (NHL): AOR 1.6 (1.1–2.3) <10 CPD: ALL: AOR 1.2 (0.8–1.6) AML: AOR 1.4 (0.7–2.9) HL: AOR 1.4 (0.7–2.6) NHL: AOR 1.5 (0.8–2.6) 10–19 CPD: ALL: AOR 1.2 (0.9–1.6) AML: AOR 1.3(0.7–2.4) HL: AOR 0.8 (0.4–1.6) NHL: AOR 1.7 (1.1–2.7) 20+ CPD: ALL: AOR 1.7 (1.3–2.1)* AML: AOR 1.7(1.0–2.9)** HL: AOR 1.2 (0.7–2.0) NHL: AOR 1.7 (1.1–2.6)***
| Telephone interview of mothers Age <15 years Matched for age, gender Adjusted for age. Gender, parental professional category, maternal age at the time of birth Maternal smoking was not associated with significant increased risk Trend analyses: *P < 0.0001 **P < 0.045 ***P < 0.01
| Low |
Schuz et al. (1999), Germany | Case control (NW and NI study) NW: 1992–97 NI: 1980–94
| 2354 cases 2588 controls 955 Acute leukaemia 955 controls 221 NHL 2540 controls
| Acute leukaemia and NHL Paternal smoking before pregnancy Acute leukaemia (ALL and AnLL) 1–10 CPD AOR 1.1 (0.8–1.5) 11–20 CPD AOR 1.0 (0.8–1.2) >20 CPD AOR 0.9 (0.7–1.2) NHL 1–10 CPD AOR 1.6 (1.0–2.5) 11–20 CPD AOR 1.1(0.7–1.6) >20 CPD AOR 1.1 (0.7–1.8)
| Questionnaire followed by telephone interview by parents Age <15years Matched for gender, age, region Adjusted for socio-economic status Not adjusted for maternal smoking, but no association with maternal smoking Study also includes estimates on CNS tumours, neuroblastoma, nephroblastoma, bone tumour, soft tissue sarcoma and no associations was found
| Medium |
Shu et al. (1996), USA | Case control 1983–88 (CCG study)
| 302 cases 203 ALL 88 AML 11 other leukaemia 558 controls Paternal smoking: 191 ALL 79 AML
| ALL and AML Only paternal smoking 1 month prior to pregnancy (A) and during pregnancy (B) A: ALL: AOR 1.56 (1.03–2.36) 1–10 CPD AOR 2.40 (1.00–5.72) 11–20 CPD AOR 1.33 (0.79–2.34) >20 CPD AOR 1.51 (0.82–2.77) AML: AOR 0.75 (0.35–1.62) 1–10 CPD AOR 0.42 (0.09–1.95) 11–20 CPD AOR 0.73 (0.27–1.94) >20 CPD AOR 1.29 (0.44–3.74) B: ALL: AOR 1.45 (0.95–2.19) AML: AOR 0.82 (0.38–1.78)
| Telephone interview with mothers and fathers (71%) Age ≤18 months Matched by age, region. Adjusted for sex, paternal age, education, maternal alcohol consumption during pregnancy Maternal smoking 1 month prior to pregnancy and during pregnancy was not associated with increased risk of ALL or AML
| Low |
Sorahan et al. (2001), UK | Case control (OSCC study) 1980–83
| 555 cases 555 controls (GP) Cases/controls: 7/9 18/16 36/35 9/5 12/3
| | Interview of parents Child age <15 years Matched on region, sex, date of birth Adjusted for maternal age, paternal age, SES, ethnicity
| Low |
Other cancers n = 19 |
Barrington-Trimis et al. (2013), USA | | 202 cases 286 controls Only paternal smoking: 25 cases 27 controls
| | In-person maternal interview Age ≤10 years Matched by age, sex, study centre Adjusted for race, sex, age at diagnosis, maternal education, birth year, centre
| Low |
Bunin et al. (1994), USA | Case control 1986–1989 | 155 AP 166 PNET 321 Controls 64/63 60/58 86/82 85/88
| | Trained interviewers with parents Child age <6 years Matched on race, year of birth, telephone area code and prefix AG: Adj. income level PNET: No adjustment
| Low |
Filippini et al. (2002), Italy | | 1218 cases 2223 controls 633/1190
| Brain tumours AOR 1.1 (0.9–1.2)
| Nine centres in 7 countries In-person interview of mostly mothers Child age 0–19 years Post hoc strata matched on age, sex and centre Adjusted for matched variables and maternal level of education
| Medium |
Gold et al. (1993), USA | | 361 cases 1083 controls Only paternal smoking: 81 cases 247 controls
| | Structured interview from each parent Age <18 years Matched for age, sex, maternal race Cases represent 85% of cases identified by the registries
| Medium |
Hu et al. (2000), China | | | Brain tumours Smoking PY AOR 1.16 (0.65–2.08)
| During hospitalization, paternal and maternal interviews by trained interviewers Age <19 years Matched for sex, age, area of residence Adjusted for maternal education, family income
| Low |
Ji et al. (1997), China | | 1981–91 642 cases 642 controls Brain tumours 107 pairs Acute leukaemia, 166 pairs Lymphoma 87 pairs
| Brain tumours Paternal smoking before conception <2 PY All cancers: AOR 1.2 (0-8-1.8) Brain tumours: AOR 1.5 (0.5–4.4) 2–5 PY All cancers: AOR 1.3 (0.9–2.0) Brain tumours: AOR 1.7 (0.5–5.8) >5 PY prior to conception All cancers: AOR 1.7 (1.2–2.5) Brain tumours: AOR 2.7 (0.8–9.9)
| Paternal and maternal interviews by trained interviewers Age <15 years Matched for sex, year of birth Adjusted for BW, income, paternal age, education and alcohol
| Low |
John et al. (1991), USA | | 1976–1983 223 cases 196 controls 60 exposed cancers 45 exposed controls
| Brain tumours Paternal smoking in preconception period in the absence of maternal smoking Brain tumours: AOR 1.6 (0.7–3.5) All cancers: AOR 1.2 (0.8–2.1)
| Personal interview Prenatal exposure Matched for age, sex, area Absence of maternal smoking: Adjusted for father’s education
| Low |
Johnson et al. (2013)USA | Case control 2000–2008 (Cases) 1994–2008 (controls)
| | | Maternal telephone interviews Age <6 years Matched for BW, gender, birth year and region Adjusted for BW, year of birth, sex, maternal race and education Not directly adjusted for maternal smoking had no influence and therefore not adjusted for
| Medium |
McCredie et al. (1994), Italy + Australia | Case control Population-based 1985–1989
| 82 cases 164 controls Ever smoking 23 cases, 28controls During pregnancy 41cases, 49controls
| | | Low |
Milne et al. (2013), Australia | Case control (Aus-CBT study) 2005–2010
| 302 cases 941 controls Preconception: 74 cases 222 controls During pregnancy 71 cases 202 controls
| Brain tumours Paternal smoking preconception AOR 0.99 (0.71–1.38) 1–14 CPD: AOR 1.31 (0.82–2.11) 15+ CPD: AOR 0.83 (0.55–1.24) Paternal smoking during pregnancy* AOR 1.04 (0.74–1.46) 1–14 CPD: AOR 1.30 (0.79–2.13) 15+ CPD: AOR 0.92 (0.61–1.38)
| Questionnaire to parents Age <15 years Matched for age, sex, state of residence Adjusted for matching variables, ethnicity, year of birth group, parental age, household income *Results shown are not adjusted for maternal smoking, but no association was found with maternal smoking Similar results when analysis was restricted to children whose other parent did not smoke (data not shown)
| Medium |
Norman et al. (1996), USA | Case control Population-based 1984–1991
| 540 cases 801 controls Ever smoked: 262 cases, 380 controls During pregnancy: 174 cases, 238 controls
| | In-person or telephone interviews of mothers and fathers (77%) Child age <20 years Matched on birth year, sex, age at diagnosis Adj. matching criteria + maternal race/ethnicity
| Medium |
Pang et al. (2003), UK | Case control (UKCCS) 1991–1996
| | Cancer Paternal smoking during the year before birth All cancers 1–19 CPD: AOR 1.11 (0.98–1.25) 20+ CPD: AOR 1.01 (0.90–1.12) CNS tumours 1–19 CPD: AOR 1.08 (0.85–1.38) 20+ CPD: AOR 1.03 (0.82–1.28)
| Personal interview with parents Age <15 years Matched for sex, age, region Adjusted for matching variables, parental age, deprivation score
| Medium |
Plichart et al. (2008), France | Case control (ESCALE study) 2003–2004
| | | Maternal telephone interview Age <15 years Matched for age, sex and number of children <15 years of age in the household Adjusted for age, gender No association between maternal smoking during pregnancy and CNS tumours.
| Low |
Sorahan et al. (1997a), UK | Case control (OSCC study) 1953–1955
| 1549 cases 1549 controls 655 cases, 618 controls
| | Interview parents, usually mothers (response rate 88%) Matched for sex, date of birth and region Adjusted for social class, parental age at birth, sib-ship position, obstetric radiography
| Medium |
Sorahan et al. (1997b), UK | Case control (OSCC study) 1971–1976
| 2587 cases 2587 controls 630 cases 573 controls
| Death of childhood cancer Paternal smoking at death of child, father only 14% of the cancers could be related to paternal smoking (all cancer and onset at all ages) ARR 1.29 (1.10–1.51)
| Interview of parents, usually mothers Child age <16 years Matched for sex, date of birth, region Adjusted for social class, parental age at birth, sib-ship position, obstetric radiography
| Medium |
Sorahan et al. (2001), UK | Case control (OSCC study) 1980–83
| 555 cases 555 controls (hospital) 555 controls (GP) Cases/GP/Hospital 26/34/27 79/60/70 114/122/121 23/32/48 28/21/40
| Childhood cancer Paternal smoking before the pregnancy ARR: <10 CPD: GP: 0.94 (0.53–1.66); Hospital: 0.92 (0.51–1.65) 10–19 CPD GP: 1.63 (1.10–2.41); Hospital: 1.06 (0.72–1.56) 20–29 CPD GP: 1.46 (1.05–2.03); Hospital: 1.11 (0.80–1.53) 30–39 CPD GP: 0.95 (0.52–1.73); Hospital: 0.45 (0.26–0.77) 40+ CPD GP: 1.77 (0.94–3.34); Hospital: 0.66 (0.39–1.11) P for trend GP P = 0.02; Hospital P = 0.16 CNS tumours also stratified on CPD, but no total ARR P for trend 0.67 Data adjusted for maternal smoking is not shown but with a significant positive trend (P = 0.03) between cancer and paternal smoking compared to GP controls
| Interview of parents Child age <15 years Matched on region, sex, date of birth Adjusted for maternal age, paternal age, SES, ethnicity
| Low |
Sorahan and Lancashire (2004), UK | Case control (OSCC study) Deaths 1953–55 1971–76 1977–81
| | | Interview parents, usually mother Child age <16 years Matched for sex, age at death, year of death Adjusted for sex, age at death, year of death, social class, sib-ship position, maternal age, paternal age, obstetric radiography
| Medium (all cancers) Low (hepatoblastoma)
|
Schuz et al. (1999), Germany | Case control (NW and NI study) NW:1992–97 NI:1980–94
| NW:1992–97 NI:1980–94 2358 cases 2588 controls 385 CNS tumours 155 neuroblastomas 2540 nephroblastomas 95 bone tumours 133 soft tissue sarcomas
| CNS tumour, Neuroblastoma, Nephroblastoma, Bone tumour, Soft tissue sarcoma Paternal smoking before pregnancy 1-10 CPD: CNS tumour: AOR 0.8 (0.5–1.2) Neuroblastoma: AOR 0.6 (0.3–1.1) Nephroblastoma: AOR 0.8 (0.4–1.4) Bone tumour: AOR 0.5 (0.2–1.2) Soft tissue sarcoma: AOR 0.8 (0.4–1.6) 11–20 CPD: CNS tumour: AOR 1.1 (0.8–1.4) Neuroblastoma: AOR 1.1 (0.7–1.6) Nephroblastoma: AOR 0.8 (0.5–1.3) Bone tumour: AOR 0.8 (0.4–1.3) Soft tissue sarcoma: AOR 1.2 (0.8–1.8) >20CPD CNS tumour: AOR 1.0 (0.7–1.4) Neuroblastoma: AOR 1.2 (0.7–2.1) Nephroblastoma: AOR 0.9 (0.5–1.6) Bone tumour: AOR 0.9 (0.4–1.8) Soft tissue sarcoma: AOR 0.9 (0.4–1.6)
| Questionnaire followed by telephone interview by parents Age <15years Matched for gender, age, region Adjusted for socio-economic status Not adjusted for maternal smoking, but no association with maternal smoking. Study also includes estimates on Acute leukaemia and NHL
| Low |
Yang et al. (2000), USA & Canada | Case control (CCG and POG studies) 1992–94
| 504 cases 504 controls Preconception 137 cases, 122 controls
| | Telephone interview with parents Child age <19 years Matched for date of birth Adjusted for gender, mother’s race, father’s education, household income in birth year Not directly adjusted maternal smoking, but no association with risk of neuroblastoma
| Medium |
Cardio-metabolic outcomes (n = 9) |
Brion et al. (2007), UK | Cohort study Avon longitudinal study
| 6396 children (Model 1) 3736 children (Model 5)
| Blood pressure at 7 years Systolic blood pressure: Model 1: Beta 0.44 (−0.07–0.95) P = 0.09 Model 5: Beta 0.17 (−0.52–0.86) P = 0.6 Diastolic blood pressure: Model 1: Beta 0.10 (−0.26–0.47) P = 0.6 Model 5: Beta −0.25 (−0.72–0.22) P = 0.3
| Questionnaires sent to partners at 18 weeks gestation on if they had smoked regularly in the last 9 months Model 1: Child age, sex Model 5: Additionally, adjusted for maternal/partner factors, social factors, breast feeding
| Medium |
de Jonge et al. (2013), US | | 5777 non-smoking mothers 3078 paternal smoking 2699 no paternal smoking
| Hypertension in daughters in adulthood (self-reported physician diagnosed) Paternal smoking during pregnancy Maternal age: ARR 1.12 (1.06–1.18) + perinatal variables: ARR 1.09 (1.03–1.15) + BW: ARR 1.08 (1.03–1.14) + adult life variables: ARR 1.08 (1.02–1.14) + body shape and weight until age: ARR 18:1.07 (1.01–1.13) + current BMI: 1.04 (0.99–1.10)
| Self-administered questionnaires to nurse’s mothers 2001 Cox proportion hazard models Multiple adj. and additional adj. for perinatal variables, adult life variables, body shape and weight until age 18 years, current BMI
| Medium |
Durmus et al. (2011), The Netherlands | Prospective cohort study 2002–2006
| | BMI at 3, 6, 12, 24, 36, 48 months Paternal smoking during pregnancy and difference in BMI at 12 months: Standardized coefficients (95% CI): 0.06 (−0.01, 0.13) 0–4 CPD 0.04 (−0.05, 0.13) ≥5 CPD 0.08 (−0.01, 0.17) P for trend P = 0.01 Similar no difference in BMI at 3, 6, 24, 36 and 48 months and no trend
| Postal questionnaires to mothers Linear mixed models Adj. Child’s age at visit, sex, paternal ethnicity and education, paternal height and weight and breast feeding (yes/no) Reporting bias Similar information completed by the fathers in 3358 participants – good agreement between mat and pat assessment
| Medium |
Florath et al. (2014), Germany | Prospective cohort Born 2000–2001
| | | During hospitalization after delivery standardized maternal interviews by trained interviewers. Follow-up to age 8 years Linear regression Adjusted for paternal BMI and education, maternal pre-pregnancy BMI, BW, monthly weight gain, exclusive breast feeding, body height, TV consumption, sports activities, diet score at 8 years and age at anthropometric measurements. Conclusion: Residual confounding conditions in smoking families by living rather than specific intrauterine exposure may account for the increased risk of offspring overweight
| Medium |
Howe et al. (2012), UK | Cohort study Avon longitudinal study
| Height: 4832 children PI: 4777 children BMI: 4534 children
| Growth 29–120 months Girls: 0.0012 (0.0021), P = 0.01 Boys: −0.0012 (0.0020), P = 0.8 Ponderal index 2–24 months: Girls: 0.0043 (0.0078), P = 0.35 Boys: −0.0011 (0.0069), P = 0.73 BMI 103–120 months: Girls: 0.0042 (0.0036), P = 0.54 Boys: 0.0033 (0.0021), P = 0.77
| Self-reported data Height 0–10 years Ponderal index 0–2 years BMI 2–10 years Maternal education, household social class, parity, maternal age, maternal height, maternal BMI, gestational age, breast feeding
| Medium |
Kwok et al. (2010), Hong Kong | Birth Cohort study 1997 | | BMI and height at child age 7 and 11 years Daily prenatal and early postnatal paternal smoking: BMI, Z-score difference, mean (95%CI) Child age 7 years: 0.10 (0.02–0.19) Child age 11 years: 0.16 (0.07–0.26) No difference in height Z scores
| Standardized self- administered questionnaire at maternal and child-health centres Daily prenatal and early postnatal paternal smoking in non-smoking women Adjusted for gender, birth order, highest parental education, mother’s place of birth, pubertal status (for 11 years) highest parental occupation, household income per person, breast feeding history, number of hospital admissions attributable to infections at 0 to 6 months
| Medium |
Leary et al. (2006), UK | Cohort study Avon longitudinal study
| Examination at 9 years 6470 children 5615 children* 3649 children**
| BMI, total fat, truncal fat, total lean (DXA scanner) at mean child age 9.9 years Paternal smoking during pregnancy *BMI: beta 0.11 (0.05, 0.17) < 0.001 *Total fat: beta 0.08 (0.03–0.13) P = 0.001
| Questionnaires to mothers Adjusted for maternal smoking *Sex, child age at DXA-scan, **Additionally adjusted for maternal, partner, social and infant feeding factors
| Medium |
Taal et al. (2013), The Netherlands | Prospective cohort study 2008–2012
| | Stroke, volume, cardiac output, larger AOD (aortic root diameter), fractional shortening at child age 6 years Regression coefficients Mean Systolic blood pressure (mmHg) −0.18 (−0.69–0.33) test for trend over smoking cat. 0.741 Mean diastolic blood pressure (mmHg) 0.12 (−0.39–0.52) test for trend over smoking cat. 0.702 Aortic root diameter (mm) Difference 0.17 (0.05–0.28)
| Questionnaires in second and third trimester Mixed models and multiple linear regression models Adjusted for maternal age, parity, mixed educational level, pre-pregnancy BMI, BP at intake, sex, GA, BW, breast feeding status, current age and BMI
| Medium |
Toschke et al. (2007), UK | Cohort study NCDS: 1958 BCS70:1970
| Two birth cohorts Total: 11 282 children NCDS: 5214 children BCS70: 6068 children
| Diabetes Mellitus Type 1 Paternal smoking OR 0.48 (0.29–0.80) Combined OR: AOR 0.44 (0.25–0.75) NCDS: AOR 0.37 (0.18–0.75) BCS70: AOR 0.54 (0.24–1.27)
| Interview of mothers NCDS: Up 16 years BCS70:5 and 10 years Adjusted for maternal smoking, sex, maternal age, paternal age, number of sibling, social class, cohort (NCDS, BCS70)
| Medium |
Neuro-developmental n = 6 |
Brion et al. (2010), UK | | | Psychological problems Paternal smoking during pregnancy Hyperactivity/attention problem** ALSPAC AOR 1.03 (0.91–1.17) Pelotas AOR 1.04 (0.71–1.50) Emotional/Internalizing problem** ALSPAC AOR 0.93 (0.82–1.06) Pelotas AOR 0.85 (0.58–1.24) Conduct/Externalizing problems** ALSPAC AOR 1.11 (0.98–1.26) Pelotas AOR 0.96 (0.66–1.41) Peer/social problems** ALSPAC AOR 1.01 (0.89–1.15) Pelotas AOR 0.98 (0.67–1.45)
| Unadjusted Maternal and paternal education, income, social class Mediators Parental psychological **Mutually adj. model incl. maternal and paternal smoking with adjustment for one another
| Medium (ALSPAC)Low (Pelotas) |
Langley et al. (2012), UK | | Fathers only smoking 6478 children ADHD diagnosis 5719 children
| ADHD Paternal smoking during pregnancy 0, 1–9, 10–19, >=20 cig per day Paternal smoking and mother non-smoking Adjusted beta=0.12 (0.04–0.20) AOR 1.42 (1.04–1.93)
| Self-reported questionnaire (mother) Child age 7–8 years Linear regression F-statistics Adjusted for sex, ethnicity, multiple pregnancy, maternal alcohol during, education, pregnancy, parental social class, maternal education
| Medium |
Nomura et al. (2010), USA | Cohort study | 209 children Fathers only smoking 40
| ADHD AOR 0.31 (0.06–1.92) ODD Not estimable ADHD and ODD AOR 0.85 (0.13–5.55)
| Interview of parents Age 3–4 years Adjusted for gender, age, race and BW of the child, maternal drinking during pregnancy, family SES, mother’s ADHD symptoms, father’s ADHD symptoms, mother and father’s smoking history
| Low |
Tang (2006), Hong Kong | | | | Self-administered questionnaire parents mostly mothers Age 2–3 years Matched for age and region Adjusted for environmental tobacco smoke (ETS) due to other household smoking other than paternal smoking, child sex, BW, breast feeding history, housing type, parents educational level and occupation
| Medium |
Tiesler et al. (2011), Germany | Cohort study Delivery 1997–1999
| | Behavioural problems Prenatal paternal smoking and environmental tobacco smoking (persons other than mothers smoking at home, ETS) Total difficult score (5/40) APOR 1.21 (0.45–3.27) Hyperactivity/inattention (8/40) APOR 2.03 (0.86–4.81)
| Self-administered questionnaires mothers 10 years follow-up Adjusted for sex, study centre, parental education, maternal age at birth, time in front of screen, single mother/father
| Low |
Zhu et al. (2014), Denmark | | 50 870 mothers participated in 7-years questionnaire 14 004 singletons with paternal smoking only 360 (2.6%) singletons with ADHD Both non-smokers ADHD: 892/49 072 (1.8%)
| | Questionnaire during pregnancy and at follow-up 7- years of age (mother) Cox regression adjusted for maternal age, parity, alcohol, SES, psychopathology, sex, diagnosis, education (registry)
| Medium |
Author, year, country
. | Study design
. | Number of deliveries and children
. | Result
. | Outcomes Adjustments
. | Quality assessment
. |
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Outcomes (Risk estimates)
. |
---|
Cancer |
Acute childhood leukaemia Meta-analyses n = 3 |
Metayer et al. (2016), USA | | Childhood Leukaemia International Consortium (CLIC) studies: Meta-analyses including 6–9 CLIC studies and 3–4 Non-CLIC studies Pooled analysis of 12 case control studies with 1330 AML 13 169 controls
| AML Paternal smoking during preconception period MA (CLIC+non-CLIC): AOR 1.19 (1.00–1.41) Pooled CLIC studies: AOR 1.18 (1.01–1.38)* Paternal smoking during pregnancy MA (CLIC+non-CLIC): AOR 1.28 (1.05–1.57) Pooled CLIC studies: AOR 1.24 (1.06–1.46)* Paternal ever smoking MA (CLIC+non-CLCI): AOR 1.18 (0.92–1.51) Pooled CLIC studies: AOR1.34 (1.11–1.62)*
| Interview with mothers and/or fathers, age <15 yrs Adjusted for age, sex, ethnicity, paternal education, study centre *Similar results for analyses including only non-smoking mothers (data not shown) Dose-response relationship with paternal smoking Maternal smoking had no effect in pooled CLIC analysis or meta-analysis and is not adjusted for High correlation between pre-and postnatal paternal smoking. Limited ability to identify specific windows of exposure
| Medium |
Milne et al. (2012), Australia | | | ALL Paternal smoking around the time of conception: Any versus none: OR 1.15 (1.06–1.24) >20 CPD: OR 1.44 (1.24–1.68)
| | Low |
Liu et al. (2011), USA | SR and meta-analysis, 18 case control studies
| Preconception: 13 studies Cases and controls: NA
| ALL Paternal smoking during preconception: AOR 1.25 (1.08–1.46)* Paternal smoking during pregnancy: AOR 1.24 (1.07–1.43) Dose-response a. >10 CPD; b. 10–19; c.>20 a. AOR 1.17 (0.9–1.54) b. AOR 1.25 (1.01–1.55) c. AOR 1.30 (1.09–1.55)
| Primarily interviews by mothers Age 18 month to 18 years Most studies matched and adjusted for potential confounders *Only 5 studies included in MA adjusted for maternal smoking Also, a positive association between ALL and paternal ever smoking and at each exposure time period examined
| Medium |
Original articles n = 19 |
Brondum et al. (1999), USA | Case control (CCG study) 1989–93
| 1618 ALL 1722 controls 450 AML 523 controls
| ALL Paternal smoking 1 month before pregnancy AOR 1.07 (0.90–1.27) Father (not mother) ever smoked (n = 1842) AOR 1.04 (0.86–1.26) AML Paternal smoking 1 month before pregnancy AOR 0.87 (0.64–1.18) Father (not mother) ever smoked (n = 517) AOR 1.32 (0.91–1.93)
| Telephone interview with parents mostly mothers Child age: ALL <15 years, AML <18 years Matched by age, race, telephone code area Adjusted for annual income, father’s and mother’s exposures, race and education No association with maternal smoking, parental years of smoking, or number of pack-years
| Medium |
Castro-Jimenez and Orozco-Vargas (2011), Colombia | | | | Face-to-face interview with parents Age <15 years Matched control sex, age, region Not adjusted for maternal smoking but of no significance
| Low |
Chang et al. (2006), USA | | | | Self-administered questionnaire/in-person interview of mothers Age <15 years Matched on age, maternal race, and Hispanic ethnicity. Adjusting for household income Maternal smoking was not associated with increased risk of ALL or AML Data included in Metayer et al. (2013)
| Low |
Farioli et al. (2014), Italy | Case control 1998–2003 (SETIL study)
| 557 cases 855 controls 1–10 CPD: 77 cases 108 controls >10 CPD: 151 cases 222 controls
| | Personal interview with parents Age <10 years Mutually adjusted models also including paternal smoking during pregnancy and maternal smoking in first trimester Child second-hand-smoking (SHS), birth order, BW, duration of breast feeding, mat and pat age, educational level, birth year mother, parental exposure benzene
| Low |
Ji et al. (1997), China | | 642 cases 642 controls No maternal smoking Acute leukaemia 166 case control pairs Lymphoma 87 case control pairs
| Cancer <2 Pack-years (PY) 2–5 PY >5 PY prior to conception Acute leukaemia AOR 2.4 (1.1–5.6)* ALL AOR 3.8 (1.3–12.3)* AML AOR 2.3 (0.4–14.8)* Lymphoma AOR 4.5 (1.2–16.8)* All cancers AOR 1.7 (1.2–2.5)*
| Paternal and maternal interviews by trained interviewers Age <15 years. Matched for sex, year of birth Adjusted for BW, income, paternal age, education and alcohol For <5 PY there were no significant risk in any of the cancers
| Low |
John et al. (1991), USA | | | Cancer Paternal smoking preconception period, absence of maternal smoking ALL: AOR 1.4 (0.6–3.1) Lymphomas: AOR 1.6 (0.5–5.4) Brain cancer: 1.6 (0.7–3.5) All cancers: AOR 1.2 (0.8–2.1)
| Personal interview Prenatal exposure Age 0–14 years Matched for age, sex, area Absence of maternal smoking: Adjusted for father’s education.
| Low |
Lee et al. (2009), Chorea | | 164 cases leukaemia 106 ALL 164 controls
| | Interview with mothers (93.5%) Age 0–18 years Matched for age and sex. Adjusted for age, gender, father’s education and birth weight Maternal smoking was too small (6.1% in controls) to be evaluated in childhood leukaemia risk and was not considered further
| Low |
MacArthur et al. (2008), Canada | | 399 cases 399 controls 109 cases 96 controls
| Acute leukaemiaAOR 0.99 (0.50–1.99) AOR 1.18 (0.70–1.20) AOR 1.14 (0.79–1.64)
APR 0.87 (0.42–1.81) AOR 1.21 (0.70–2.08) AOR 1.15 (0.79–1.67)
AOR 2.98 (0.70–12.75) AOR 0.93 (0.25–3.45) AOR 0.90 (0.34–2.38)
| Personal interviews with each child parents Age 0–14 years Matched for age, gender, area Conditional logistic regression Maternal age, mat education, household income, ethnicity, and no of residences since birth Not directly adjusted maternal Smoking, but maternal risk estimates did not change when paternal smoking patterns were considered
| Low |
Magnani et al. (1990) | Case control 1974–1980 1981–1984
| 142 ALL 22 AnLL 19 (NHL) 307 controls
| | | Low |
Mattioli et al. (2014), Italy | Case control (SETIL study) 1998–2003
| | Acute non-Lymphatic Leukaemia (AnLL) Paternal smoking in the conception period 1–10 CPD: AOR 1.34 (0.65–2.76) ≥11 CPD: AOR 1.79 (1.01–3.15)
| Personal interview of parents Age 0–10 years Matched for date of birth, sex, residence Inverse probability weighting adjusting for sex, provenience, birth order, BW, breast feeding, parental educational level, age, birth year, occupational exposure to benzene Not directly adjusted maternal smoking but no association on AnLL and maternal smoking during pregnancy
| Low |
Menegaux et al. (2007), France | Case control 1995–1998 | 472 cases 407 ALL 62 AML 3 other 567 controls
| Childhood acute leukaemia (ALL and AML) Paternal smoking 3 months before pregnancy All acute leukaemia ≤20 CPD: AOR 1.2 (0.9–1.6) >20CPD: AOR 1.0 (0.6–1.7) ALL ≤20 CPD: AOR 1.2 (0.9–1.6) >20 CPD: AOR 1.2 (0.7–2.0) AML ≤20 CPD: AOR 0.9 (0.5–1.7) >20 CPD: AOR 0.2 (0.02–1.7)
| Standardised self- administered questionnaire to mothers Age <15 years Matched for age, gender, region Adjusted for matched age, gender, region, socio-professional category, birth order Not directly adjusted for maternal smoking but not significant
| Low |
Metayer et al. (2013), USA | Case control (NCCLS study) 1996–2008
| 767 ALL 135 AML 1139 controls
| ALL and AML Paternal prenatal smoking (3 month before and/or during pregnancy) ALL: AOR 1.17 (0.91–1.50)* AML: AOR 1.36 (0.82–2.24)* Paternal prenatal smoking and child’s passive smoking ALL: AOR 0.94 (0.69–1.27)** AML: AOR 1.14 (0.55–2.39)**
| Phase 1: Self-administered questionnaire/ Phase 2: In-person interview of mainly mothers Age < 15 years Matched on age, maternal race, and Hispanic ethnicity Adjusting for matching variables and household income *Not adjusted for maternal smoking but no significant association with ALL or AML **adjusted for maternal prenatal smoking Expansion of Chang et al. (2006)
| Low |
Milne et al. (2012), Australia | Case control (Aus-ALL study) 2003–2006
| | ALL Paternal smoking during conception year: Any: AOR 1.22 (0.92–1.61) 1–14 CPD: AOR 1.00 (0.66–1.52) >15 CPD: AOR 1.35 (0.98–1.86)
| Self-administered questionnaires from both parents Age <15 years Matched by age, sex, state of residence Adjusted for matching variables, paternal age, parental education, ethnicity Maternal smoking was not associated with ALL and paternal smoking unchanged when adjusted for maternal smoking (data not shown)
| Low |
Orsi et al. (2015), France | | 747 CL 636 ALL 100 AML 1421 controls
| All leukaemia (AL), ALL, AML Paternal preconception smoking: AL: AOR 1.3 (1.0–1.6) ALL: AOR 1.2 (0.9–1.6) AML: AOR 1.6 (1.0–2.8) Paternal smoking during pregnancy: AL: AOR 1.3 (1.1–1.6) ALL: AOR 1.3 (1.0–1.6) AML: AOR 1.6 (1.0–2.5)
| Telephone interview with parents, mostly mothers Age <15 years Matched for age, sex Adjusted for age, sex, mother’s age and education, birth order and maternal smoking
| Low |
Pang et al. (2003), UK | Case control (UKCCS) 1991–96
| 3585 case fathers 6987 control fathers
| Leukaemia Paternal preconception smoking 1–19 CPD: AOR 1.12 (0.96–1.32) 20+ CPD: AOR 1.01 (0.87–1.17) ALL: AOR 1.04 (0.91–1.18) AML: AOR 1.07 (0.80–1.43)
| Personal interview with parents Age <15 years Matched for sex, age, region Adjusted for matching variables, parental age, deprivation score
| Medium |
Rudant et al. (2008), France | Case control (ESCALE study) 2003–4
| 647 ALL 102 AML 1681 controls 128 HL 848 controls 164 NHL 1312 controls
| Hematopoietic malignancies Paternal smoking from the year prior to the child’s birth to the interview ALL: AOR 1.4 (1.1–1.7) AML: AOR 1.5 (1.0–2.3) Hodgkin’s lymphoma (HL): AOR 1.2 (0.8–1.7) Non-Hodgkin’s lymphoma (NHL): AOR 1.6 (1.1–2.3) <10 CPD: ALL: AOR 1.2 (0.8–1.6) AML: AOR 1.4 (0.7–2.9) HL: AOR 1.4 (0.7–2.6) NHL: AOR 1.5 (0.8–2.6) 10–19 CPD: ALL: AOR 1.2 (0.9–1.6) AML: AOR 1.3(0.7–2.4) HL: AOR 0.8 (0.4–1.6) NHL: AOR 1.7 (1.1–2.7) 20+ CPD: ALL: AOR 1.7 (1.3–2.1)* AML: AOR 1.7(1.0–2.9)** HL: AOR 1.2 (0.7–2.0) NHL: AOR 1.7 (1.1–2.6)***
| Telephone interview of mothers Age <15 years Matched for age, gender Adjusted for age. Gender, parental professional category, maternal age at the time of birth Maternal smoking was not associated with significant increased risk Trend analyses: *P < 0.0001 **P < 0.045 ***P < 0.01
| Low |
Schuz et al. (1999), Germany | Case control (NW and NI study) NW: 1992–97 NI: 1980–94
| 2354 cases 2588 controls 955 Acute leukaemia 955 controls 221 NHL 2540 controls
| Acute leukaemia and NHL Paternal smoking before pregnancy Acute leukaemia (ALL and AnLL) 1–10 CPD AOR 1.1 (0.8–1.5) 11–20 CPD AOR 1.0 (0.8–1.2) >20 CPD AOR 0.9 (0.7–1.2) NHL 1–10 CPD AOR 1.6 (1.0–2.5) 11–20 CPD AOR 1.1(0.7–1.6) >20 CPD AOR 1.1 (0.7–1.8)
| Questionnaire followed by telephone interview by parents Age <15years Matched for gender, age, region Adjusted for socio-economic status Not adjusted for maternal smoking, but no association with maternal smoking Study also includes estimates on CNS tumours, neuroblastoma, nephroblastoma, bone tumour, soft tissue sarcoma and no associations was found
| Medium |
Shu et al. (1996), USA | Case control 1983–88 (CCG study)
| 302 cases 203 ALL 88 AML 11 other leukaemia 558 controls Paternal smoking: 191 ALL 79 AML
| ALL and AML Only paternal smoking 1 month prior to pregnancy (A) and during pregnancy (B) A: ALL: AOR 1.56 (1.03–2.36) 1–10 CPD AOR 2.40 (1.00–5.72) 11–20 CPD AOR 1.33 (0.79–2.34) >20 CPD AOR 1.51 (0.82–2.77) AML: AOR 0.75 (0.35–1.62) 1–10 CPD AOR 0.42 (0.09–1.95) 11–20 CPD AOR 0.73 (0.27–1.94) >20 CPD AOR 1.29 (0.44–3.74) B: ALL: AOR 1.45 (0.95–2.19) AML: AOR 0.82 (0.38–1.78)
| Telephone interview with mothers and fathers (71%) Age ≤18 months Matched by age, region. Adjusted for sex, paternal age, education, maternal alcohol consumption during pregnancy Maternal smoking 1 month prior to pregnancy and during pregnancy was not associated with increased risk of ALL or AML
| Low |
Sorahan et al. (2001), UK | Case control (OSCC study) 1980–83
| 555 cases 555 controls (GP) Cases/controls: 7/9 18/16 36/35 9/5 12/3
| | Interview of parents Child age <15 years Matched on region, sex, date of birth Adjusted for maternal age, paternal age, SES, ethnicity
| Low |
Other cancers n = 19 |
Barrington-Trimis et al. (2013), USA | | 202 cases 286 controls Only paternal smoking: 25 cases 27 controls
| | In-person maternal interview Age ≤10 years Matched by age, sex, study centre Adjusted for race, sex, age at diagnosis, maternal education, birth year, centre
| Low |
Bunin et al. (1994), USA | Case control 1986–1989 | 155 AP 166 PNET 321 Controls 64/63 60/58 86/82 85/88
| | Trained interviewers with parents Child age <6 years Matched on race, year of birth, telephone area code and prefix AG: Adj. income level PNET: No adjustment
| Low |
Filippini et al. (2002), Italy | | 1218 cases 2223 controls 633/1190
| Brain tumours AOR 1.1 (0.9–1.2)
| Nine centres in 7 countries In-person interview of mostly mothers Child age 0–19 years Post hoc strata matched on age, sex and centre Adjusted for matched variables and maternal level of education
| Medium |
Gold et al. (1993), USA | | 361 cases 1083 controls Only paternal smoking: 81 cases 247 controls
| | Structured interview from each parent Age <18 years Matched for age, sex, maternal race Cases represent 85% of cases identified by the registries
| Medium |
Hu et al. (2000), China | | | Brain tumours Smoking PY AOR 1.16 (0.65–2.08)
| During hospitalization, paternal and maternal interviews by trained interviewers Age <19 years Matched for sex, age, area of residence Adjusted for maternal education, family income
| Low |
Ji et al. (1997), China | | 1981–91 642 cases 642 controls Brain tumours 107 pairs Acute leukaemia, 166 pairs Lymphoma 87 pairs
| Brain tumours Paternal smoking before conception <2 PY All cancers: AOR 1.2 (0-8-1.8) Brain tumours: AOR 1.5 (0.5–4.4) 2–5 PY All cancers: AOR 1.3 (0.9–2.0) Brain tumours: AOR 1.7 (0.5–5.8) >5 PY prior to conception All cancers: AOR 1.7 (1.2–2.5) Brain tumours: AOR 2.7 (0.8–9.9)
| Paternal and maternal interviews by trained interviewers Age <15 years Matched for sex, year of birth Adjusted for BW, income, paternal age, education and alcohol
| Low |
John et al. (1991), USA | | 1976–1983 223 cases 196 controls 60 exposed cancers 45 exposed controls
| Brain tumours Paternal smoking in preconception period in the absence of maternal smoking Brain tumours: AOR 1.6 (0.7–3.5) All cancers: AOR 1.2 (0.8–2.1)
| Personal interview Prenatal exposure Matched for age, sex, area Absence of maternal smoking: Adjusted for father’s education
| Low |
Johnson et al. (2013)USA | Case control 2000–2008 (Cases) 1994–2008 (controls)
| | | Maternal telephone interviews Age <6 years Matched for BW, gender, birth year and region Adjusted for BW, year of birth, sex, maternal race and education Not directly adjusted for maternal smoking had no influence and therefore not adjusted for
| Medium |
McCredie et al. (1994), Italy + Australia | Case control Population-based 1985–1989
| 82 cases 164 controls Ever smoking 23 cases, 28controls During pregnancy 41cases, 49controls
| | | Low |
Milne et al. (2013), Australia | Case control (Aus-CBT study) 2005–2010
| 302 cases 941 controls Preconception: 74 cases 222 controls During pregnancy 71 cases 202 controls
| Brain tumours Paternal smoking preconception AOR 0.99 (0.71–1.38) 1–14 CPD: AOR 1.31 (0.82–2.11) 15+ CPD: AOR 0.83 (0.55–1.24) Paternal smoking during pregnancy* AOR 1.04 (0.74–1.46) 1–14 CPD: AOR 1.30 (0.79–2.13) 15+ CPD: AOR 0.92 (0.61–1.38)
| Questionnaire to parents Age <15 years Matched for age, sex, state of residence Adjusted for matching variables, ethnicity, year of birth group, parental age, household income *Results shown are not adjusted for maternal smoking, but no association was found with maternal smoking Similar results when analysis was restricted to children whose other parent did not smoke (data not shown)
| Medium |
Norman et al. (1996), USA | Case control Population-based 1984–1991
| 540 cases 801 controls Ever smoked: 262 cases, 380 controls During pregnancy: 174 cases, 238 controls
| | In-person or telephone interviews of mothers and fathers (77%) Child age <20 years Matched on birth year, sex, age at diagnosis Adj. matching criteria + maternal race/ethnicity
| Medium |
Pang et al. (2003), UK | Case control (UKCCS) 1991–1996
| | Cancer Paternal smoking during the year before birth All cancers 1–19 CPD: AOR 1.11 (0.98–1.25) 20+ CPD: AOR 1.01 (0.90–1.12) CNS tumours 1–19 CPD: AOR 1.08 (0.85–1.38) 20+ CPD: AOR 1.03 (0.82–1.28)
| Personal interview with parents Age <15 years Matched for sex, age, region Adjusted for matching variables, parental age, deprivation score
| Medium |
Plichart et al. (2008), France | Case control (ESCALE study) 2003–2004
| | | Maternal telephone interview Age <15 years Matched for age, sex and number of children <15 years of age in the household Adjusted for age, gender No association between maternal smoking during pregnancy and CNS tumours.
| Low |
Sorahan et al. (1997a), UK | Case control (OSCC study) 1953–1955
| 1549 cases 1549 controls 655 cases, 618 controls
| | Interview parents, usually mothers (response rate 88%) Matched for sex, date of birth and region Adjusted for social class, parental age at birth, sib-ship position, obstetric radiography
| Medium |
Sorahan et al. (1997b), UK | Case control (OSCC study) 1971–1976
| 2587 cases 2587 controls 630 cases 573 controls
| Death of childhood cancer Paternal smoking at death of child, father only 14% of the cancers could be related to paternal smoking (all cancer and onset at all ages) ARR 1.29 (1.10–1.51)
| Interview of parents, usually mothers Child age <16 years Matched for sex, date of birth, region Adjusted for social class, parental age at birth, sib-ship position, obstetric radiography
| Medium |
Sorahan et al. (2001), UK | Case control (OSCC study) 1980–83
| 555 cases 555 controls (hospital) 555 controls (GP) Cases/GP/Hospital 26/34/27 79/60/70 114/122/121 23/32/48 28/21/40
| Childhood cancer Paternal smoking before the pregnancy ARR: <10 CPD: GP: 0.94 (0.53–1.66); Hospital: 0.92 (0.51–1.65) 10–19 CPD GP: 1.63 (1.10–2.41); Hospital: 1.06 (0.72–1.56) 20–29 CPD GP: 1.46 (1.05–2.03); Hospital: 1.11 (0.80–1.53) 30–39 CPD GP: 0.95 (0.52–1.73); Hospital: 0.45 (0.26–0.77) 40+ CPD GP: 1.77 (0.94–3.34); Hospital: 0.66 (0.39–1.11) P for trend GP P = 0.02; Hospital P = 0.16 CNS tumours also stratified on CPD, but no total ARR P for trend 0.67 Data adjusted for maternal smoking is not shown but with a significant positive trend (P = 0.03) between cancer and paternal smoking compared to GP controls
| Interview of parents Child age <15 years Matched on region, sex, date of birth Adjusted for maternal age, paternal age, SES, ethnicity
| Low |
Sorahan and Lancashire (2004), UK | Case control (OSCC study) Deaths 1953–55 1971–76 1977–81
| | | Interview parents, usually mother Child age <16 years Matched for sex, age at death, year of death Adjusted for sex, age at death, year of death, social class, sib-ship position, maternal age, paternal age, obstetric radiography
| Medium (all cancers) Low (hepatoblastoma)
|
Schuz et al. (1999), Germany | Case control (NW and NI study) NW:1992–97 NI:1980–94
| NW:1992–97 NI:1980–94 2358 cases 2588 controls 385 CNS tumours 155 neuroblastomas 2540 nephroblastomas 95 bone tumours 133 soft tissue sarcomas
| CNS tumour, Neuroblastoma, Nephroblastoma, Bone tumour, Soft tissue sarcoma Paternal smoking before pregnancy 1-10 CPD: CNS tumour: AOR 0.8 (0.5–1.2) Neuroblastoma: AOR 0.6 (0.3–1.1) Nephroblastoma: AOR 0.8 (0.4–1.4) Bone tumour: AOR 0.5 (0.2–1.2) Soft tissue sarcoma: AOR 0.8 (0.4–1.6) 11–20 CPD: CNS tumour: AOR 1.1 (0.8–1.4) Neuroblastoma: AOR 1.1 (0.7–1.6) Nephroblastoma: AOR 0.8 (0.5–1.3) Bone tumour: AOR 0.8 (0.4–1.3) Soft tissue sarcoma: AOR 1.2 (0.8–1.8) >20CPD CNS tumour: AOR 1.0 (0.7–1.4) Neuroblastoma: AOR 1.2 (0.7–2.1) Nephroblastoma: AOR 0.9 (0.5–1.6) Bone tumour: AOR 0.9 (0.4–1.8) Soft tissue sarcoma: AOR 0.9 (0.4–1.6)
| Questionnaire followed by telephone interview by parents Age <15years Matched for gender, age, region Adjusted for socio-economic status Not adjusted for maternal smoking, but no association with maternal smoking. Study also includes estimates on Acute leukaemia and NHL
| Low |
Yang et al. (2000), USA & Canada | Case control (CCG and POG studies) 1992–94
| 504 cases 504 controls Preconception 137 cases, 122 controls
| | Telephone interview with parents Child age <19 years Matched for date of birth Adjusted for gender, mother’s race, father’s education, household income in birth year Not directly adjusted maternal smoking, but no association with risk of neuroblastoma
| Medium |
Cardio-metabolic outcomes (n = 9) |
Brion et al. (2007), UK | Cohort study Avon longitudinal study
| 6396 children (Model 1) 3736 children (Model 5)
| Blood pressure at 7 years Systolic blood pressure: Model 1: Beta 0.44 (−0.07–0.95) P = 0.09 Model 5: Beta 0.17 (−0.52–0.86) P = 0.6 Diastolic blood pressure: Model 1: Beta 0.10 (−0.26–0.47) P = 0.6 Model 5: Beta −0.25 (−0.72–0.22) P = 0.3
| Questionnaires sent to partners at 18 weeks gestation on if they had smoked regularly in the last 9 months Model 1: Child age, sex Model 5: Additionally, adjusted for maternal/partner factors, social factors, breast feeding
| Medium |
de Jonge et al. (2013), US | | 5777 non-smoking mothers 3078 paternal smoking 2699 no paternal smoking
| Hypertension in daughters in adulthood (self-reported physician diagnosed) Paternal smoking during pregnancy Maternal age: ARR 1.12 (1.06–1.18) + perinatal variables: ARR 1.09 (1.03–1.15) + BW: ARR 1.08 (1.03–1.14) + adult life variables: ARR 1.08 (1.02–1.14) + body shape and weight until age: ARR 18:1.07 (1.01–1.13) + current BMI: 1.04 (0.99–1.10)
| Self-administered questionnaires to nurse’s mothers 2001 Cox proportion hazard models Multiple adj. and additional adj. for perinatal variables, adult life variables, body shape and weight until age 18 years, current BMI
| Medium |
Durmus et al. (2011), The Netherlands | Prospective cohort study 2002–2006
| | BMI at 3, 6, 12, 24, 36, 48 months Paternal smoking during pregnancy and difference in BMI at 12 months: Standardized coefficients (95% CI): 0.06 (−0.01, 0.13) 0–4 CPD 0.04 (−0.05, 0.13) ≥5 CPD 0.08 (−0.01, 0.17) P for trend P = 0.01 Similar no difference in BMI at 3, 6, 24, 36 and 48 months and no trend
| Postal questionnaires to mothers Linear mixed models Adj. Child’s age at visit, sex, paternal ethnicity and education, paternal height and weight and breast feeding (yes/no) Reporting bias Similar information completed by the fathers in 3358 participants – good agreement between mat and pat assessment
| Medium |
Florath et al. (2014), Germany | Prospective cohort Born 2000–2001
| | | During hospitalization after delivery standardized maternal interviews by trained interviewers. Follow-up to age 8 years Linear regression Adjusted for paternal BMI and education, maternal pre-pregnancy BMI, BW, monthly weight gain, exclusive breast feeding, body height, TV consumption, sports activities, diet score at 8 years and age at anthropometric measurements. Conclusion: Residual confounding conditions in smoking families by living rather than specific intrauterine exposure may account for the increased risk of offspring overweight
| Medium |
Howe et al. (2012), UK | Cohort study Avon longitudinal study
| Height: 4832 children PI: 4777 children BMI: 4534 children
| Growth 29–120 months Girls: 0.0012 (0.0021), P = 0.01 Boys: −0.0012 (0.0020), P = 0.8 Ponderal index 2–24 months: Girls: 0.0043 (0.0078), P = 0.35 Boys: −0.0011 (0.0069), P = 0.73 BMI 103–120 months: Girls: 0.0042 (0.0036), P = 0.54 Boys: 0.0033 (0.0021), P = 0.77
| Self-reported data Height 0–10 years Ponderal index 0–2 years BMI 2–10 years Maternal education, household social class, parity, maternal age, maternal height, maternal BMI, gestational age, breast feeding
| Medium |
Kwok et al. (2010), Hong Kong | Birth Cohort study 1997 | | BMI and height at child age 7 and 11 years Daily prenatal and early postnatal paternal smoking: BMI, Z-score difference, mean (95%CI) Child age 7 years: 0.10 (0.02–0.19) Child age 11 years: 0.16 (0.07–0.26) No difference in height Z scores
| Standardized self- administered questionnaire at maternal and child-health centres Daily prenatal and early postnatal paternal smoking in non-smoking women Adjusted for gender, birth order, highest parental education, mother’s place of birth, pubertal status (for 11 years) highest parental occupation, household income per person, breast feeding history, number of hospital admissions attributable to infections at 0 to 6 months
| Medium |
Leary et al. (2006), UK | Cohort study Avon longitudinal study
| Examination at 9 years 6470 children 5615 children* 3649 children**
| BMI, total fat, truncal fat, total lean (DXA scanner) at mean child age 9.9 years Paternal smoking during pregnancy *BMI: beta 0.11 (0.05, 0.17) < 0.001 *Total fat: beta 0.08 (0.03–0.13) P = 0.001
| Questionnaires to mothers Adjusted for maternal smoking *Sex, child age at DXA-scan, **Additionally adjusted for maternal, partner, social and infant feeding factors
| Medium |
Taal et al. (2013), The Netherlands | Prospective cohort study 2008–2012
| | Stroke, volume, cardiac output, larger AOD (aortic root diameter), fractional shortening at child age 6 years Regression coefficients Mean Systolic blood pressure (mmHg) −0.18 (−0.69–0.33) test for trend over smoking cat. 0.741 Mean diastolic blood pressure (mmHg) 0.12 (−0.39–0.52) test for trend over smoking cat. 0.702 Aortic root diameter (mm) Difference 0.17 (0.05–0.28)
| Questionnaires in second and third trimester Mixed models and multiple linear regression models Adjusted for maternal age, parity, mixed educational level, pre-pregnancy BMI, BP at intake, sex, GA, BW, breast feeding status, current age and BMI
| Medium |
Toschke et al. (2007), UK | Cohort study NCDS: 1958 BCS70:1970
| Two birth cohorts Total: 11 282 children NCDS: 5214 children BCS70: 6068 children
| Diabetes Mellitus Type 1 Paternal smoking OR 0.48 (0.29–0.80) Combined OR: AOR 0.44 (0.25–0.75) NCDS: AOR 0.37 (0.18–0.75) BCS70: AOR 0.54 (0.24–1.27)
| Interview of mothers NCDS: Up 16 years BCS70:5 and 10 years Adjusted for maternal smoking, sex, maternal age, paternal age, number of sibling, social class, cohort (NCDS, BCS70)
| Medium |
Neuro-developmental n = 6 |
Brion et al. (2010), UK | | | Psychological problems Paternal smoking during pregnancy Hyperactivity/attention problem** ALSPAC AOR 1.03 (0.91–1.17) Pelotas AOR 1.04 (0.71–1.50) Emotional/Internalizing problem** ALSPAC AOR 0.93 (0.82–1.06) Pelotas AOR 0.85 (0.58–1.24) Conduct/Externalizing problems** ALSPAC AOR 1.11 (0.98–1.26) Pelotas AOR 0.96 (0.66–1.41) Peer/social problems** ALSPAC AOR 1.01 (0.89–1.15) Pelotas AOR 0.98 (0.67–1.45)
| Unadjusted Maternal and paternal education, income, social class Mediators Parental psychological **Mutually adj. model incl. maternal and paternal smoking with adjustment for one another
| Medium (ALSPAC)Low (Pelotas) |
Langley et al. (2012), UK | | Fathers only smoking 6478 children ADHD diagnosis 5719 children
| ADHD Paternal smoking during pregnancy 0, 1–9, 10–19, >=20 cig per day Paternal smoking and mother non-smoking Adjusted beta=0.12 (0.04–0.20) AOR 1.42 (1.04–1.93)
| Self-reported questionnaire (mother) Child age 7–8 years Linear regression F-statistics Adjusted for sex, ethnicity, multiple pregnancy, maternal alcohol during, education, pregnancy, parental social class, maternal education
| Medium |
Nomura et al. (2010), USA | Cohort study | 209 children Fathers only smoking 40
| ADHD AOR 0.31 (0.06–1.92) ODD Not estimable ADHD and ODD AOR 0.85 (0.13–5.55)
| Interview of parents Age 3–4 years Adjusted for gender, age, race and BW of the child, maternal drinking during pregnancy, family SES, mother’s ADHD symptoms, father’s ADHD symptoms, mother and father’s smoking history
| Low |
Tang (2006), Hong Kong | | | | Self-administered questionnaire parents mostly mothers Age 2–3 years Matched for age and region Adjusted for environmental tobacco smoke (ETS) due to other household smoking other than paternal smoking, child sex, BW, breast feeding history, housing type, parents educational level and occupation
| Medium |
Tiesler et al. (2011), Germany | Cohort study Delivery 1997–1999
| | Behavioural problems Prenatal paternal smoking and environmental tobacco smoking (persons other than mothers smoking at home, ETS) Total difficult score (5/40) APOR 1.21 (0.45–3.27) Hyperactivity/inattention (8/40) APOR 2.03 (0.86–4.81)
| Self-administered questionnaires mothers 10 years follow-up Adjusted for sex, study centre, parental education, maternal age at birth, time in front of screen, single mother/father
| Low |
Zhu et al. (2014), Denmark | | 50 870 mothers participated in 7-years questionnaire 14 004 singletons with paternal smoking only 360 (2.6%) singletons with ADHD Both non-smokers ADHD: 892/49 072 (1.8%)
| | Questionnaire during pregnancy and at follow-up 7- years of age (mother) Cox regression adjusted for maternal age, parity, alcohol, SES, psychopathology, sex, diagnosis, education (registry)
| Medium |
Table XStudies on the association of paternal smoking with long-term outcomes in offspring.
Author, year, country
. | Study design
. | Number of deliveries and children
. | Result
. | Outcomes Adjustments
. | Quality assessment
. |
---|
Outcomes (Risk estimates)
. |
---|
Cancer |
Acute childhood leukaemia Meta-analyses n = 3 |
Metayer et al. (2016), USA | | Childhood Leukaemia International Consortium (CLIC) studies: Meta-analyses including 6–9 CLIC studies and 3–4 Non-CLIC studies Pooled analysis of 12 case control studies with 1330 AML 13 169 controls
| AML Paternal smoking during preconception period MA (CLIC+non-CLIC): AOR 1.19 (1.00–1.41) Pooled CLIC studies: AOR 1.18 (1.01–1.38)* Paternal smoking during pregnancy MA (CLIC+non-CLIC): AOR 1.28 (1.05–1.57) Pooled CLIC studies: AOR 1.24 (1.06–1.46)* Paternal ever smoking MA (CLIC+non-CLCI): AOR 1.18 (0.92–1.51) Pooled CLIC studies: AOR1.34 (1.11–1.62)*
| Interview with mothers and/or fathers, age <15 yrs Adjusted for age, sex, ethnicity, paternal education, study centre *Similar results for analyses including only non-smoking mothers (data not shown) Dose-response relationship with paternal smoking Maternal smoking had no effect in pooled CLIC analysis or meta-analysis and is not adjusted for High correlation between pre-and postnatal paternal smoking. Limited ability to identify specific windows of exposure
| Medium |
Milne et al. (2012), Australia | | | ALL Paternal smoking around the time of conception: Any versus none: OR 1.15 (1.06–1.24) >20 CPD: OR 1.44 (1.24–1.68)
| | Low |
Liu et al. (2011), USA | SR and meta-analysis, 18 case control studies
| Preconception: 13 studies Cases and controls: NA
| ALL Paternal smoking during preconception: AOR 1.25 (1.08–1.46)* Paternal smoking during pregnancy: AOR 1.24 (1.07–1.43) Dose-response a. >10 CPD; b. 10–19; c.>20 a. AOR 1.17 (0.9–1.54) b. AOR 1.25 (1.01–1.55) c. AOR 1.30 (1.09–1.55)
| Primarily interviews by mothers Age 18 month to 18 years Most studies matched and adjusted for potential confounders *Only 5 studies included in MA adjusted for maternal smoking Also, a positive association between ALL and paternal ever smoking and at each exposure time period examined
| Medium |
Original articles n = 19 |
Brondum et al. (1999), USA | Case control (CCG study) 1989–93
| 1618 ALL 1722 controls 450 AML 523 controls
| ALL Paternal smoking 1 month before pregnancy AOR 1.07 (0.90–1.27) Father (not mother) ever smoked (n = 1842) AOR 1.04 (0.86–1.26) AML Paternal smoking 1 month before pregnancy AOR 0.87 (0.64–1.18) Father (not mother) ever smoked (n = 517) AOR 1.32 (0.91–1.93)
| Telephone interview with parents mostly mothers Child age: ALL <15 years, AML <18 years Matched by age, race, telephone code area Adjusted for annual income, father’s and mother’s exposures, race and education No association with maternal smoking, parental years of smoking, or number of pack-years
| Medium |
Castro-Jimenez and Orozco-Vargas (2011), Colombia | | | | Face-to-face interview with parents Age <15 years Matched control sex, age, region Not adjusted for maternal smoking but of no significance
| Low |
Chang et al. (2006), USA | | | | Self-administered questionnaire/in-person interview of mothers Age <15 years Matched on age, maternal race, and Hispanic ethnicity. Adjusting for household income Maternal smoking was not associated with increased risk of ALL or AML Data included in Metayer et al. (2013)
| Low |
Farioli et al. (2014), Italy | Case control 1998–2003 (SETIL study)
| 557 cases 855 controls 1–10 CPD: 77 cases 108 controls >10 CPD: 151 cases 222 controls
| | Personal interview with parents Age <10 years Mutually adjusted models also including paternal smoking during pregnancy and maternal smoking in first trimester Child second-hand-smoking (SHS), birth order, BW, duration of breast feeding, mat and pat age, educational level, birth year mother, parental exposure benzene
| Low |
Ji et al. (1997), China | | 642 cases 642 controls No maternal smoking Acute leukaemia 166 case control pairs Lymphoma 87 case control pairs
| Cancer <2 Pack-years (PY) 2–5 PY >5 PY prior to conception Acute leukaemia AOR 2.4 (1.1–5.6)* ALL AOR 3.8 (1.3–12.3)* AML AOR 2.3 (0.4–14.8)* Lymphoma AOR 4.5 (1.2–16.8)* All cancers AOR 1.7 (1.2–2.5)*
| Paternal and maternal interviews by trained interviewers Age <15 years. Matched for sex, year of birth Adjusted for BW, income, paternal age, education and alcohol For <5 PY there were no significant risk in any of the cancers
| Low |
John et al. (1991), USA | | | Cancer Paternal smoking preconception period, absence of maternal smoking ALL: AOR 1.4 (0.6–3.1) Lymphomas: AOR 1.6 (0.5–5.4) Brain cancer: 1.6 (0.7–3.5) All cancers: AOR 1.2 (0.8–2.1)
| Personal interview Prenatal exposure Age 0–14 years Matched for age, sex, area Absence of maternal smoking: Adjusted for father’s education.
| Low |
Lee et al. (2009), Chorea | | 164 cases leukaemia 106 ALL 164 controls
| | Interview with mothers (93.5%) Age 0–18 years Matched for age and sex. Adjusted for age, gender, father’s education and birth weight Maternal smoking was too small (6.1% in controls) to be evaluated in childhood leukaemia risk and was not considered further
| Low |
MacArthur et al. (2008), Canada | | 399 cases 399 controls 109 cases 96 controls
| Acute leukaemiaAOR 0.99 (0.50–1.99) AOR 1.18 (0.70–1.20) AOR 1.14 (0.79–1.64)
APR 0.87 (0.42–1.81) AOR 1.21 (0.70–2.08) AOR 1.15 (0.79–1.67)
AOR 2.98 (0.70–12.75) AOR 0.93 (0.25–3.45) AOR 0.90 (0.34–2.38)
| Personal interviews with each child parents Age 0–14 years Matched for age, gender, area Conditional logistic regression Maternal age, mat education, household income, ethnicity, and no of residences since birth Not directly adjusted maternal Smoking, but maternal risk estimates did not change when paternal smoking patterns were considered
| Low |
Magnani et al. (1990) | Case control 1974–1980 1981–1984
| 142 ALL 22 AnLL 19 (NHL) 307 controls
| | | Low |
Mattioli et al. (2014), Italy | Case control (SETIL study) 1998–2003
| | Acute non-Lymphatic Leukaemia (AnLL) Paternal smoking in the conception period 1–10 CPD: AOR 1.34 (0.65–2.76) ≥11 CPD: AOR 1.79 (1.01–3.15)
| Personal interview of parents Age 0–10 years Matched for date of birth, sex, residence Inverse probability weighting adjusting for sex, provenience, birth order, BW, breast feeding, parental educational level, age, birth year, occupational exposure to benzene Not directly adjusted maternal smoking but no association on AnLL and maternal smoking during pregnancy
| Low |
Menegaux et al. (2007), France | Case control 1995–1998 | 472 cases 407 ALL 62 AML 3 other 567 controls
| Childhood acute leukaemia (ALL and AML) Paternal smoking 3 months before pregnancy All acute leukaemia ≤20 CPD: AOR 1.2 (0.9–1.6) >20CPD: AOR 1.0 (0.6–1.7) ALL ≤20 CPD: AOR 1.2 (0.9–1.6) >20 CPD: AOR 1.2 (0.7–2.0) AML ≤20 CPD: AOR 0.9 (0.5–1.7) >20 CPD: AOR 0.2 (0.02–1.7)
| Standardised self- administered questionnaire to mothers Age <15 years Matched for age, gender, region Adjusted for matched age, gender, region, socio-professional category, birth order Not directly adjusted for maternal smoking but not significant
| Low |
Metayer et al. (2013), USA | Case control (NCCLS study) 1996–2008
| 767 ALL 135 AML 1139 controls
| ALL and AML Paternal prenatal smoking (3 month before and/or during pregnancy) ALL: AOR 1.17 (0.91–1.50)* AML: AOR 1.36 (0.82–2.24)* Paternal prenatal smoking and child’s passive smoking ALL: AOR 0.94 (0.69–1.27)** AML: AOR 1.14 (0.55–2.39)**
| Phase 1: Self-administered questionnaire/ Phase 2: In-person interview of mainly mothers Age < 15 years Matched on age, maternal race, and Hispanic ethnicity Adjusting for matching variables and household income *Not adjusted for maternal smoking but no significant association with ALL or AML **adjusted for maternal prenatal smoking Expansion of Chang et al. (2006)
| Low |
Milne et al. (2012), Australia | Case control (Aus-ALL study) 2003–2006
| | ALL Paternal smoking during conception year: Any: AOR 1.22 (0.92–1.61) 1–14 CPD: AOR 1.00 (0.66–1.52) >15 CPD: AOR 1.35 (0.98–1.86)
| Self-administered questionnaires from both parents Age <15 years Matched by age, sex, state of residence Adjusted for matching variables, paternal age, parental education, ethnicity Maternal smoking was not associated with ALL and paternal smoking unchanged when adjusted for maternal smoking (data not shown)
| Low |
Orsi et al. (2015), France | | 747 CL 636 ALL 100 AML 1421 controls
| All leukaemia (AL), ALL, AML Paternal preconception smoking: AL: AOR 1.3 (1.0–1.6) ALL: AOR 1.2 (0.9–1.6) AML: AOR 1.6 (1.0–2.8) Paternal smoking during pregnancy: AL: AOR 1.3 (1.1–1.6) ALL: AOR 1.3 (1.0–1.6) AML: AOR 1.6 (1.0–2.5)
| Telephone interview with parents, mostly mothers Age <15 years Matched for age, sex Adjusted for age, sex, mother’s age and education, birth order and maternal smoking
| Low |
Pang et al. (2003), UK | Case control (UKCCS) 1991–96
| 3585 case fathers 6987 control fathers
| Leukaemia Paternal preconception smoking 1–19 CPD: AOR 1.12 (0.96–1.32) 20+ CPD: AOR 1.01 (0.87–1.17) ALL: AOR 1.04 (0.91–1.18) AML: AOR 1.07 (0.80–1.43)
| Personal interview with parents Age <15 years Matched for sex, age, region Adjusted for matching variables, parental age, deprivation score
| Medium |
Rudant et al. (2008), France | Case control (ESCALE study) 2003–4
| 647 ALL 102 AML 1681 controls 128 HL 848 controls 164 NHL 1312 controls
| Hematopoietic malignancies Paternal smoking from the year prior to the child’s birth to the interview ALL: AOR 1.4 (1.1–1.7) AML: AOR 1.5 (1.0–2.3) Hodgkin’s lymphoma (HL): AOR 1.2 (0.8–1.7) Non-Hodgkin’s lymphoma (NHL): AOR 1.6 (1.1–2.3) <10 CPD: ALL: AOR 1.2 (0.8–1.6) AML: AOR 1.4 (0.7–2.9) HL: AOR 1.4 (0.7–2.6) NHL: AOR 1.5 (0.8–2.6) 10–19 CPD: ALL: AOR 1.2 (0.9–1.6) AML: AOR 1.3(0.7–2.4) HL: AOR 0.8 (0.4–1.6) NHL: AOR 1.7 (1.1–2.7) 20+ CPD: ALL: AOR 1.7 (1.3–2.1)* AML: AOR 1.7(1.0–2.9)** HL: AOR 1.2 (0.7–2.0) NHL: AOR 1.7 (1.1–2.6)***
| Telephone interview of mothers Age <15 years Matched for age, gender Adjusted for age. Gender, parental professional category, maternal age at the time of birth Maternal smoking was not associated with significant increased risk Trend analyses: *P < 0.0001 **P < 0.045 ***P < 0.01
| Low |
Schuz et al. (1999), Germany | Case control (NW and NI study) NW: 1992–97 NI: 1980–94
| 2354 cases 2588 controls 955 Acute leukaemia 955 controls 221 NHL 2540 controls
| Acute leukaemia and NHL Paternal smoking before pregnancy Acute leukaemia (ALL and AnLL) 1–10 CPD AOR 1.1 (0.8–1.5) 11–20 CPD AOR 1.0 (0.8–1.2) >20 CPD AOR 0.9 (0.7–1.2) NHL 1–10 CPD AOR 1.6 (1.0–2.5) 11–20 CPD AOR 1.1(0.7–1.6) >20 CPD AOR 1.1 (0.7–1.8)
| Questionnaire followed by telephone interview by parents Age <15years Matched for gender, age, region Adjusted for socio-economic status Not adjusted for maternal smoking, but no association with maternal smoking Study also includes estimates on CNS tumours, neuroblastoma, nephroblastoma, bone tumour, soft tissue sarcoma and no associations was found
| Medium |
Shu et al. (1996), USA | Case control 1983–88 (CCG study)
| 302 cases 203 ALL 88 AML 11 other leukaemia 558 controls Paternal smoking: 191 ALL 79 AML
| ALL and AML Only paternal smoking 1 month prior to pregnancy (A) and during pregnancy (B) A: ALL: AOR 1.56 (1.03–2.36) 1–10 CPD AOR 2.40 (1.00–5.72) 11–20 CPD AOR 1.33 (0.79–2.34) >20 CPD AOR 1.51 (0.82–2.77) AML: AOR 0.75 (0.35–1.62) 1–10 CPD AOR 0.42 (0.09–1.95) 11–20 CPD AOR 0.73 (0.27–1.94) >20 CPD AOR 1.29 (0.44–3.74) B: ALL: AOR 1.45 (0.95–2.19) AML: AOR 0.82 (0.38–1.78)
| Telephone interview with mothers and fathers (71%) Age ≤18 months Matched by age, region. Adjusted for sex, paternal age, education, maternal alcohol consumption during pregnancy Maternal smoking 1 month prior to pregnancy and during pregnancy was not associated with increased risk of ALL or AML
| Low |
Sorahan et al. (2001), UK | Case control (OSCC study) 1980–83
| 555 cases 555 controls (GP) Cases/controls: 7/9 18/16 36/35 9/5 12/3
| | Interview of parents Child age <15 years Matched on region, sex, date of birth Adjusted for maternal age, paternal age, SES, ethnicity
| Low |
Other cancers n = 19 |
Barrington-Trimis et al. (2013), USA | | 202 cases 286 controls Only paternal smoking: 25 cases 27 controls
| | In-person maternal interview Age ≤10 years Matched by age, sex, study centre Adjusted for race, sex, age at diagnosis, maternal education, birth year, centre
| Low |
Bunin et al. (1994), USA | Case control 1986–1989 | 155 AP 166 PNET 321 Controls 64/63 60/58 86/82 85/88
| | Trained interviewers with parents Child age <6 years Matched on race, year of birth, telephone area code and prefix AG: Adj. income level PNET: No adjustment
| Low |
Filippini et al. (2002), Italy | | 1218 cases 2223 controls 633/1190
| Brain tumours AOR 1.1 (0.9–1.2)
| Nine centres in 7 countries In-person interview of mostly mothers Child age 0–19 years Post hoc strata matched on age, sex and centre Adjusted for matched variables and maternal level of education
| Medium |
Gold et al. (1993), USA | | 361 cases 1083 controls Only paternal smoking: 81 cases 247 controls
| | Structured interview from each parent Age <18 years Matched for age, sex, maternal race Cases represent 85% of cases identified by the registries
| Medium |
Hu et al. (2000), China | | | Brain tumours Smoking PY AOR 1.16 (0.65–2.08)
| During hospitalization, paternal and maternal interviews by trained interviewers Age <19 years Matched for sex, age, area of residence Adjusted for maternal education, family income
| Low |
Ji et al. (1997), China | | 1981–91 642 cases 642 controls Brain tumours 107 pairs Acute leukaemia, 166 pairs Lymphoma 87 pairs
| Brain tumours Paternal smoking before conception <2 PY All cancers: AOR 1.2 (0-8-1.8) Brain tumours: AOR 1.5 (0.5–4.4) 2–5 PY All cancers: AOR 1.3 (0.9–2.0) Brain tumours: AOR 1.7 (0.5–5.8) >5 PY prior to conception All cancers: AOR 1.7 (1.2–2.5) Brain tumours: AOR 2.7 (0.8–9.9)
| Paternal and maternal interviews by trained interviewers Age <15 years Matched for sex, year of birth Adjusted for BW, income, paternal age, education and alcohol
| Low |
John et al. (1991), USA | | 1976–1983 223 cases 196 controls 60 exposed cancers 45 exposed controls
| Brain tumours Paternal smoking in preconception period in the absence of maternal smoking Brain tumours: AOR 1.6 (0.7–3.5) All cancers: AOR 1.2 (0.8–2.1)
| Personal interview Prenatal exposure Matched for age, sex, area Absence of maternal smoking: Adjusted for father’s education
| Low |
Johnson et al. (2013)USA | Case control 2000–2008 (Cases) 1994–2008 (controls)
| | | Maternal telephone interviews Age <6 years Matched for BW, gender, birth year and region Adjusted for BW, year of birth, sex, maternal race and education Not directly adjusted for maternal smoking had no influence and therefore not adjusted for
| Medium |
McCredie et al. (1994), Italy + Australia | Case control Population-based 1985–1989
| 82 cases 164 controls Ever smoking 23 cases, 28controls During pregnancy 41cases, 49controls
| | | Low |
Milne et al. (2013), Australia | Case control (Aus-CBT study) 2005–2010
| 302 cases 941 controls Preconception: 74 cases 222 controls During pregnancy 71 cases 202 controls
| Brain tumours Paternal smoking preconception AOR 0.99 (0.71–1.38) 1–14 CPD: AOR 1.31 (0.82–2.11) 15+ CPD: AOR 0.83 (0.55–1.24) Paternal smoking during pregnancy* AOR 1.04 (0.74–1.46) 1–14 CPD: AOR 1.30 (0.79–2.13) 15+ CPD: AOR 0.92 (0.61–1.38)
| Questionnaire to parents Age <15 years Matched for age, sex, state of residence Adjusted for matching variables, ethnicity, year of birth group, parental age, household income *Results shown are not adjusted for maternal smoking, but no association was found with maternal smoking Similar results when analysis was restricted to children whose other parent did not smoke (data not shown)
| Medium |
Norman et al. (1996), USA | Case control Population-based 1984–1991
| 540 cases 801 controls Ever smoked: 262 cases, 380 controls During pregnancy: 174 cases, 238 controls
| | In-person or telephone interviews of mothers and fathers (77%) Child age <20 years Matched on birth year, sex, age at diagnosis Adj. matching criteria + maternal race/ethnicity
| Medium |
Pang et al. (2003), UK | Case control (UKCCS) 1991–1996
| | Cancer Paternal smoking during the year before birth All cancers 1–19 CPD: AOR 1.11 (0.98–1.25) 20+ CPD: AOR 1.01 (0.90–1.12) CNS tumours 1–19 CPD: AOR 1.08 (0.85–1.38) 20+ CPD: AOR 1.03 (0.82–1.28)
| Personal interview with parents Age <15 years Matched for sex, age, region Adjusted for matching variables, parental age, deprivation score
| Medium |
Plichart et al. (2008), France | Case control (ESCALE study) 2003–2004
| | | Maternal telephone interview Age <15 years Matched for age, sex and number of children <15 years of age in the household Adjusted for age, gender No association between maternal smoking during pregnancy and CNS tumours.
| Low |
Sorahan et al. (1997a), UK | Case control (OSCC study) 1953–1955
| 1549 cases 1549 controls 655 cases, 618 controls
| | Interview parents, usually mothers (response rate 88%) Matched for sex, date of birth and region Adjusted for social class, parental age at birth, sib-ship position, obstetric radiography
| Medium |
Sorahan et al. (1997b), UK | Case control (OSCC study) 1971–1976
| 2587 cases 2587 controls 630 cases 573 controls
| Death of childhood cancer Paternal smoking at death of child, father only 14% of the cancers could be related to paternal smoking (all cancer and onset at all ages) ARR 1.29 (1.10–1.51)
| Interview of parents, usually mothers Child age <16 years Matched for sex, date of birth, region Adjusted for social class, parental age at birth, sib-ship position, obstetric radiography
| Medium |
Sorahan et al. (2001), UK | Case control (OSCC study) 1980–83
| 555 cases 555 controls (hospital) 555 controls (GP) Cases/GP/Hospital 26/34/27 79/60/70 114/122/121 23/32/48 28/21/40
| Childhood cancer Paternal smoking before the pregnancy ARR: <10 CPD: GP: 0.94 (0.53–1.66); Hospital: 0.92 (0.51–1.65) 10–19 CPD GP: 1.63 (1.10–2.41); Hospital: 1.06 (0.72–1.56) 20–29 CPD GP: 1.46 (1.05–2.03); Hospital: 1.11 (0.80–1.53) 30–39 CPD GP: 0.95 (0.52–1.73); Hospital: 0.45 (0.26–0.77) 40+ CPD GP: 1.77 (0.94–3.34); Hospital: 0.66 (0.39–1.11) P for trend GP P = 0.02; Hospital P = 0.16 CNS tumours also stratified on CPD, but no total ARR P for trend 0.67 Data adjusted for maternal smoking is not shown but with a significant positive trend (P = 0.03) between cancer and paternal smoking compared to GP controls
| Interview of parents Child age <15 years Matched on region, sex, date of birth Adjusted for maternal age, paternal age, SES, ethnicity
| Low |
Sorahan and Lancashire (2004), UK | Case control (OSCC study) Deaths 1953–55 1971–76 1977–81
| | | Interview parents, usually mother Child age <16 years Matched for sex, age at death, year of death Adjusted for sex, age at death, year of death, social class, sib-ship position, maternal age, paternal age, obstetric radiography
| Medium (all cancers) Low (hepatoblastoma)
|
Schuz et al. (1999), Germany | Case control (NW and NI study) NW:1992–97 NI:1980–94
| NW:1992–97 NI:1980–94 2358 cases 2588 controls 385 CNS tumours 155 neuroblastomas 2540 nephroblastomas 95 bone tumours 133 soft tissue sarcomas
| CNS tumour, Neuroblastoma, Nephroblastoma, Bone tumour, Soft tissue sarcoma Paternal smoking before pregnancy 1-10 CPD: CNS tumour: AOR 0.8 (0.5–1.2) Neuroblastoma: AOR 0.6 (0.3–1.1) Nephroblastoma: AOR 0.8 (0.4–1.4) Bone tumour: AOR 0.5 (0.2–1.2) Soft tissue sarcoma: AOR 0.8 (0.4–1.6) 11–20 CPD: CNS tumour: AOR 1.1 (0.8–1.4) Neuroblastoma: AOR 1.1 (0.7–1.6) Nephroblastoma: AOR 0.8 (0.5–1.3) Bone tumour: AOR 0.8 (0.4–1.3) Soft tissue sarcoma: AOR 1.2 (0.8–1.8) >20CPD CNS tumour: AOR 1.0 (0.7–1.4) Neuroblastoma: AOR 1.2 (0.7–2.1) Nephroblastoma: AOR 0.9 (0.5–1.6) Bone tumour: AOR 0.9 (0.4–1.8) Soft tissue sarcoma: AOR 0.9 (0.4–1.6)
| Questionnaire followed by telephone interview by parents Age <15years Matched for gender, age, region Adjusted for socio-economic status Not adjusted for maternal smoking, but no association with maternal smoking. Study also includes estimates on Acute leukaemia and NHL
| Low |
Yang et al. (2000), USA & Canada | Case control (CCG and POG studies) 1992–94
| 504 cases 504 controls Preconception 137 cases, 122 controls
| | Telephone interview with parents Child age <19 years Matched for date of birth Adjusted for gender, mother’s race, father’s education, household income in birth year Not directly adjusted maternal smoking, but no association with risk of neuroblastoma
| Medium |
Cardio-metabolic outcomes (n = 9) |
Brion et al. (2007), UK | Cohort study Avon longitudinal study
| 6396 children (Model 1) 3736 children (Model 5)
| Blood pressure at 7 years Systolic blood pressure: Model 1: Beta 0.44 (−0.07–0.95) P = 0.09 Model 5: Beta 0.17 (−0.52–0.86) P = 0.6 Diastolic blood pressure: Model 1: Beta 0.10 (−0.26–0.47) P = 0.6 Model 5: Beta −0.25 (−0.72–0.22) P = 0.3
| Questionnaires sent to partners at 18 weeks gestation on if they had smoked regularly in the last 9 months Model 1: Child age, sex Model 5: Additionally, adjusted for maternal/partner factors, social factors, breast feeding
| Medium |
de Jonge et al. (2013), US | | 5777 non-smoking mothers 3078 paternal smoking 2699 no paternal smoking
| Hypertension in daughters in adulthood (self-reported physician diagnosed) Paternal smoking during pregnancy Maternal age: ARR 1.12 (1.06–1.18) + perinatal variables: ARR 1.09 (1.03–1.15) + BW: ARR 1.08 (1.03–1.14) + adult life variables: ARR 1.08 (1.02–1.14) + body shape and weight until age: ARR 18:1.07 (1.01–1.13) + current BMI: 1.04 (0.99–1.10)
| Self-administered questionnaires to nurse’s mothers 2001 Cox proportion hazard models Multiple adj. and additional adj. for perinatal variables, adult life variables, body shape and weight until age 18 years, current BMI
| Medium |
Durmus et al. (2011), The Netherlands | Prospective cohort study 2002–2006
| | BMI at 3, 6, 12, 24, 36, 48 months Paternal smoking during pregnancy and difference in BMI at 12 months: Standardized coefficients (95% CI): 0.06 (−0.01, 0.13) 0–4 CPD 0.04 (−0.05, 0.13) ≥5 CPD 0.08 (−0.01, 0.17) P for trend P = 0.01 Similar no difference in BMI at 3, 6, 24, 36 and 48 months and no trend
| Postal questionnaires to mothers Linear mixed models Adj. Child’s age at visit, sex, paternal ethnicity and education, paternal height and weight and breast feeding (yes/no) Reporting bias Similar information completed by the fathers in 3358 participants – good agreement between mat and pat assessment
| Medium |
Florath et al. (2014), Germany | Prospective cohort Born 2000–2001
| | | During hospitalization after delivery standardized maternal interviews by trained interviewers. Follow-up to age 8 years Linear regression Adjusted for paternal BMI and education, maternal pre-pregnancy BMI, BW, monthly weight gain, exclusive breast feeding, body height, TV consumption, sports activities, diet score at 8 years and age at anthropometric measurements. Conclusion: Residual confounding conditions in smoking families by living rather than specific intrauterine exposure may account for the increased risk of offspring overweight
| Medium |
Howe et al. (2012), UK | Cohort study Avon longitudinal study
| Height: 4832 children PI: 4777 children BMI: 4534 children
| Growth 29–120 months Girls: 0.0012 (0.0021), P = 0.01 Boys: −0.0012 (0.0020), P = 0.8 Ponderal index 2–24 months: Girls: 0.0043 (0.0078), P = 0.35 Boys: −0.0011 (0.0069), P = 0.73 BMI 103–120 months: Girls: 0.0042 (0.0036), P = 0.54 Boys: 0.0033 (0.0021), P = 0.77
| Self-reported data Height 0–10 years Ponderal index 0–2 years BMI 2–10 years Maternal education, household social class, parity, maternal age, maternal height, maternal BMI, gestational age, breast feeding
| Medium |
Kwok et al. (2010), Hong Kong | Birth Cohort study 1997 | | BMI and height at child age 7 and 11 years Daily prenatal and early postnatal paternal smoking: BMI, Z-score difference, mean (95%CI) Child age 7 years: 0.10 (0.02–0.19) Child age 11 years: 0.16 (0.07–0.26) No difference in height Z scores
| Standardized self- administered questionnaire at maternal and child-health centres Daily prenatal and early postnatal paternal smoking in non-smoking women Adjusted for gender, birth order, highest parental education, mother’s place of birth, pubertal status (for 11 years) highest parental occupation, household income per person, breast feeding history, number of hospital admissions attributable to infections at 0 to 6 months
| Medium |
Leary et al. (2006), UK | Cohort study Avon longitudinal study
| Examination at 9 years 6470 children 5615 children* 3649 children**
| BMI, total fat, truncal fat, total lean (DXA scanner) at mean child age 9.9 years Paternal smoking during pregnancy *BMI: beta 0.11 (0.05, 0.17) < 0.001 *Total fat: beta 0.08 (0.03–0.13) P = 0.001
| Questionnaires to mothers Adjusted for maternal smoking *Sex, child age at DXA-scan, **Additionally adjusted for maternal, partner, social and infant feeding factors
| Medium |
Taal et al. (2013), The Netherlands | Prospective cohort study 2008–2012
| | Stroke, volume, cardiac output, larger AOD (aortic root diameter), fractional shortening at child age 6 years Regression coefficients Mean Systolic blood pressure (mmHg) −0.18 (−0.69–0.33) test for trend over smoking cat. 0.741 Mean diastolic blood pressure (mmHg) 0.12 (−0.39–0.52) test for trend over smoking cat. 0.702 Aortic root diameter (mm) Difference 0.17 (0.05–0.28)
| Questionnaires in second and third trimester Mixed models and multiple linear regression models Adjusted for maternal age, parity, mixed educational level, pre-pregnancy BMI, BP at intake, sex, GA, BW, breast feeding status, current age and BMI
| Medium |
Toschke et al. (2007), UK | Cohort study NCDS: 1958 BCS70:1970
| Two birth cohorts Total: 11 282 children NCDS: 5214 children BCS70: 6068 children
| Diabetes Mellitus Type 1 Paternal smoking OR 0.48 (0.29–0.80) Combined OR: AOR 0.44 (0.25–0.75) NCDS: AOR 0.37 (0.18–0.75) BCS70: AOR 0.54 (0.24–1.27)
| Interview of mothers NCDS: Up 16 years BCS70:5 and 10 years Adjusted for maternal smoking, sex, maternal age, paternal age, number of sibling, social class, cohort (NCDS, BCS70)
| Medium |
Neuro-developmental n = 6 |
Brion et al. (2010), UK | | | Psychological problems Paternal smoking during pregnancy Hyperactivity/attention problem** ALSPAC AOR 1.03 (0.91–1.17) Pelotas AOR 1.04 (0.71–1.50) Emotional/Internalizing problem** ALSPAC AOR 0.93 (0.82–1.06) Pelotas AOR 0.85 (0.58–1.24) Conduct/Externalizing problems** ALSPAC AOR 1.11 (0.98–1.26) Pelotas AOR 0.96 (0.66–1.41) Peer/social problems** ALSPAC AOR 1.01 (0.89–1.15) Pelotas AOR 0.98 (0.67–1.45)
| Unadjusted Maternal and paternal education, income, social class Mediators Parental psychological **Mutually adj. model incl. maternal and paternal smoking with adjustment for one another
| Medium (ALSPAC)Low (Pelotas) |
Langley et al. (2012), UK | | Fathers only smoking 6478 children ADHD diagnosis 5719 children
| ADHD Paternal smoking during pregnancy 0, 1–9, 10–19, >=20 cig per day Paternal smoking and mother non-smoking Adjusted beta=0.12 (0.04–0.20) AOR 1.42 (1.04–1.93)
| Self-reported questionnaire (mother) Child age 7–8 years Linear regression F-statistics Adjusted for sex, ethnicity, multiple pregnancy, maternal alcohol during, education, pregnancy, parental social class, maternal education
| Medium |
Nomura et al. (2010), USA | Cohort study | 209 children Fathers only smoking 40
| ADHD AOR 0.31 (0.06–1.92) ODD Not estimable ADHD and ODD AOR 0.85 (0.13–5.55)
| Interview of parents Age 3–4 years Adjusted for gender, age, race and BW of the child, maternal drinking during pregnancy, family SES, mother’s ADHD symptoms, father’s ADHD symptoms, mother and father’s smoking history
| Low |
Tang (2006), Hong Kong | | | | Self-administered questionnaire parents mostly mothers Age 2–3 years Matched for age and region Adjusted for environmental tobacco smoke (ETS) due to other household smoking other than paternal smoking, child sex, BW, breast feeding history, housing type, parents educational level and occupation
| Medium |
Tiesler et al. (2011), Germany | Cohort study Delivery 1997–1999
| | Behavioural problems Prenatal paternal smoking and environmental tobacco smoking (persons other than mothers smoking at home, ETS) Total difficult score (5/40) APOR 1.21 (0.45–3.27) Hyperactivity/inattention (8/40) APOR 2.03 (0.86–4.81)
| Self-administered questionnaires mothers 10 years follow-up Adjusted for sex, study centre, parental education, maternal age at birth, time in front of screen, single mother/father
| Low |
Zhu et al. (2014), Denmark | | 50 870 mothers participated in 7-years questionnaire 14 004 singletons with paternal smoking only 360 (2.6%) singletons with ADHD Both non-smokers ADHD: 892/49 072 (1.8%)
| | Questionnaire during pregnancy and at follow-up 7- years of age (mother) Cox regression adjusted for maternal age, parity, alcohol, SES, psychopathology, sex, diagnosis, education (registry)
| Medium |
Author, year, country
. | Study design
. | Number of deliveries and children
. | Result
. | Outcomes Adjustments
. | Quality assessment
. |
---|
Outcomes (Risk estimates)
. |
---|
Cancer |
Acute childhood leukaemia Meta-analyses n = 3 |
Metayer et al. (2016), USA | | Childhood Leukaemia International Consortium (CLIC) studies: Meta-analyses including 6–9 CLIC studies and 3–4 Non-CLIC studies Pooled analysis of 12 case control studies with 1330 AML 13 169 controls
| AML Paternal smoking during preconception period MA (CLIC+non-CLIC): AOR 1.19 (1.00–1.41) Pooled CLIC studies: AOR 1.18 (1.01–1.38)* Paternal smoking during pregnancy MA (CLIC+non-CLIC): AOR 1.28 (1.05–1.57) Pooled CLIC studies: AOR 1.24 (1.06–1.46)* Paternal ever smoking MA (CLIC+non-CLCI): AOR 1.18 (0.92–1.51) Pooled CLIC studies: AOR1.34 (1.11–1.62)*
| Interview with mothers and/or fathers, age <15 yrs Adjusted for age, sex, ethnicity, paternal education, study centre *Similar results for analyses including only non-smoking mothers (data not shown) Dose-response relationship with paternal smoking Maternal smoking had no effect in pooled CLIC analysis or meta-analysis and is not adjusted for High correlation between pre-and postnatal paternal smoking. Limited ability to identify specific windows of exposure
| Medium |
Milne et al. (2012), Australia | | | ALL Paternal smoking around the time of conception: Any versus none: OR 1.15 (1.06–1.24) >20 CPD: OR 1.44 (1.24–1.68)
| | Low |
Liu et al. (2011), USA | SR and meta-analysis, 18 case control studies
| Preconception: 13 studies Cases and controls: NA
| ALL Paternal smoking during preconception: AOR 1.25 (1.08–1.46)* Paternal smoking during pregnancy: AOR 1.24 (1.07–1.43) Dose-response a. >10 CPD; b. 10–19; c.>20 a. AOR 1.17 (0.9–1.54) b. AOR 1.25 (1.01–1.55) c. AOR 1.30 (1.09–1.55)
| Primarily interviews by mothers Age 18 month to 18 years Most studies matched and adjusted for potential confounders *Only 5 studies included in MA adjusted for maternal smoking Also, a positive association between ALL and paternal ever smoking and at each exposure time period examined
| Medium |
Original articles n = 19 |
Brondum et al. (1999), USA | Case control (CCG study) 1989–93
| 1618 ALL 1722 controls 450 AML 523 controls
| ALL Paternal smoking 1 month before pregnancy AOR 1.07 (0.90–1.27) Father (not mother) ever smoked (n = 1842) AOR 1.04 (0.86–1.26) AML Paternal smoking 1 month before pregnancy AOR 0.87 (0.64–1.18) Father (not mother) ever smoked (n = 517) AOR 1.32 (0.91–1.93)
| Telephone interview with parents mostly mothers Child age: ALL <15 years, AML <18 years Matched by age, race, telephone code area Adjusted for annual income, father’s and mother’s exposures, race and education No association with maternal smoking, parental years of smoking, or number of pack-years
| Medium |
Castro-Jimenez and Orozco-Vargas (2011), Colombia | | | | Face-to-face interview with parents Age <15 years Matched control sex, age, region Not adjusted for maternal smoking but of no significance
| Low |
Chang et al. (2006), USA | | | | Self-administered questionnaire/in-person interview of mothers Age <15 years Matched on age, maternal race, and Hispanic ethnicity. Adjusting for household income Maternal smoking was not associated with increased risk of ALL or AML Data included in Metayer et al. (2013)
| Low |
Farioli et al. (2014), Italy | Case control 1998–2003 (SETIL study)
| 557 cases 855 controls 1–10 CPD: 77 cases 108 controls >10 CPD: 151 cases 222 controls
| | Personal interview with parents Age <10 years Mutually adjusted models also including paternal smoking during pregnancy and maternal smoking in first trimester Child second-hand-smoking (SHS), birth order, BW, duration of breast feeding, mat and pat age, educational level, birth year mother, parental exposure benzene
| Low |
Ji et al. (1997), China | | 642 cases 642 controls No maternal smoking Acute leukaemia 166 case control pairs Lymphoma 87 case control pairs
| Cancer <2 Pack-years (PY) 2–5 PY >5 PY prior to conception Acute leukaemia AOR 2.4 (1.1–5.6)* ALL AOR 3.8 (1.3–12.3)* AML AOR 2.3 (0.4–14.8)* Lymphoma AOR 4.5 (1.2–16.8)* All cancers AOR 1.7 (1.2–2.5)*
| Paternal and maternal interviews by trained interviewers Age <15 years. Matched for sex, year of birth Adjusted for BW, income, paternal age, education and alcohol For <5 PY there were no significant risk in any of the cancers
| Low |
John et al. (1991), USA | | | Cancer Paternal smoking preconception period, absence of maternal smoking ALL: AOR 1.4 (0.6–3.1) Lymphomas: AOR 1.6 (0.5–5.4) Brain cancer: 1.6 (0.7–3.5) All cancers: AOR 1.2 (0.8–2.1)
| Personal interview Prenatal exposure Age 0–14 years Matched for age, sex, area Absence of maternal smoking: Adjusted for father’s education.
| Low |
Lee et al. (2009), Chorea | | 164 cases leukaemia 106 ALL 164 controls
| | Interview with mothers (93.5%) Age 0–18 years Matched for age and sex. Adjusted for age, gender, father’s education and birth weight Maternal smoking was too small (6.1% in controls) to be evaluated in childhood leukaemia risk and was not considered further
| Low |
MacArthur et al. (2008), Canada | | 399 cases 399 controls 109 cases 96 controls
| Acute leukaemiaAOR 0.99 (0.50–1.99) AOR 1.18 (0.70–1.20) AOR 1.14 (0.79–1.64)
APR 0.87 (0.42–1.81) AOR 1.21 (0.70–2.08) AOR 1.15 (0.79–1.67)
AOR 2.98 (0.70–12.75) AOR 0.93 (0.25–3.45) AOR 0.90 (0.34–2.38)
| Personal interviews with each child parents Age 0–14 years Matched for age, gender, area Conditional logistic regression Maternal age, mat education, household income, ethnicity, and no of residences since birth Not directly adjusted maternal Smoking, but maternal risk estimates did not change when paternal smoking patterns were considered
| Low |
Magnani et al. (1990) | Case control 1974–1980 1981–1984
| 142 ALL 22 AnLL 19 (NHL) 307 controls
| | | Low |
Mattioli et al. (2014), Italy | Case control (SETIL study) 1998–2003
| | Acute non-Lymphatic Leukaemia (AnLL) Paternal smoking in the conception period 1–10 CPD: AOR 1.34 (0.65–2.76) ≥11 CPD: AOR 1.79 (1.01–3.15)
| Personal interview of parents Age 0–10 years Matched for date of birth, sex, residence Inverse probability weighting adjusting for sex, provenience, birth order, BW, breast feeding, parental educational level, age, birth year, occupational exposure to benzene Not directly adjusted maternal smoking but no association on AnLL and maternal smoking during pregnancy
| Low |
Menegaux et al. (2007), France | Case control 1995–1998 | 472 cases 407 ALL 62 AML 3 other 567 controls
| Childhood acute leukaemia (ALL and AML) Paternal smoking 3 months before pregnancy All acute leukaemia ≤20 CPD: AOR 1.2 (0.9–1.6) >20CPD: AOR 1.0 (0.6–1.7) ALL ≤20 CPD: AOR 1.2 (0.9–1.6) >20 CPD: AOR 1.2 (0.7–2.0) AML ≤20 CPD: AOR 0.9 (0.5–1.7) >20 CPD: AOR 0.2 (0.02–1.7)
| Standardised self- administered questionnaire to mothers Age <15 years Matched for age, gender, region Adjusted for matched age, gender, region, socio-professional category, birth order Not directly adjusted for maternal smoking but not significant
| Low |
Metayer et al. (2013), USA | Case control (NCCLS study) 1996–2008
| 767 ALL 135 AML 1139 controls
| ALL and AML Paternal prenatal smoking (3 month before and/or during pregnancy) ALL: AOR 1.17 (0.91–1.50)* AML: AOR 1.36 (0.82–2.24)* Paternal prenatal smoking and child’s passive smoking ALL: AOR 0.94 (0.69–1.27)** AML: AOR 1.14 (0.55–2.39)**
| Phase 1: Self-administered questionnaire/ Phase 2: In-person interview of mainly mothers Age < 15 years Matched on age, maternal race, and Hispanic ethnicity Adjusting for matching variables and household income *Not adjusted for maternal smoking but no significant association with ALL or AML **adjusted for maternal prenatal smoking Expansion of Chang et al. (2006)
| Low |
Milne et al. (2012), Australia | Case control (Aus-ALL study) 2003–2006
| | ALL Paternal smoking during conception year: Any: AOR 1.22 (0.92–1.61) 1–14 CPD: AOR 1.00 (0.66–1.52) >15 CPD: AOR 1.35 (0.98–1.86)
| Self-administered questionnaires from both parents Age <15 years Matched by age, sex, state of residence Adjusted for matching variables, paternal age, parental education, ethnicity Maternal smoking was not associated with ALL and paternal smoking unchanged when adjusted for maternal smoking (data not shown)
| Low |
Orsi et al. (2015), France | | 747 CL 636 ALL 100 AML 1421 controls
| All leukaemia (AL), ALL, AML Paternal preconception smoking: AL: AOR 1.3 (1.0–1.6) ALL: AOR 1.2 (0.9–1.6) AML: AOR 1.6 (1.0–2.8) Paternal smoking during pregnancy: AL: AOR 1.3 (1.1–1.6) ALL: AOR 1.3 (1.0–1.6) AML: AOR 1.6 (1.0–2.5)
| Telephone interview with parents, mostly mothers Age <15 years Matched for age, sex Adjusted for age, sex, mother’s age and education, birth order and maternal smoking
| Low |
Pang et al. (2003), UK | Case control (UKCCS) 1991–96
| 3585 case fathers 6987 control fathers
| Leukaemia Paternal preconception smoking 1–19 CPD: AOR 1.12 (0.96–1.32) 20+ CPD: AOR 1.01 (0.87–1.17) ALL: AOR 1.04 (0.91–1.18) AML: AOR 1.07 (0.80–1.43)
| Personal interview with parents Age <15 years Matched for sex, age, region Adjusted for matching variables, parental age, deprivation score
| Medium |
Rudant et al. (2008), France | Case control (ESCALE study) 2003–4
| 647 ALL 102 AML 1681 controls 128 HL 848 controls 164 NHL 1312 controls
| Hematopoietic malignancies Paternal smoking from the year prior to the child’s birth to the interview ALL: AOR 1.4 (1.1–1.7) AML: AOR 1.5 (1.0–2.3) Hodgkin’s lymphoma (HL): AOR 1.2 (0.8–1.7) Non-Hodgkin’s lymphoma (NHL): AOR 1.6 (1.1–2.3) <10 CPD: ALL: AOR 1.2 (0.8–1.6) AML: AOR 1.4 (0.7–2.9) HL: AOR 1.4 (0.7–2.6) NHL: AOR 1.5 (0.8–2.6) 10–19 CPD: ALL: AOR 1.2 (0.9–1.6) AML: AOR 1.3(0.7–2.4) HL: AOR 0.8 (0.4–1.6) NHL: AOR 1.7 (1.1–2.7) 20+ CPD: ALL: AOR 1.7 (1.3–2.1)* AML: AOR 1.7(1.0–2.9)** HL: AOR 1.2 (0.7–2.0) NHL: AOR 1.7 (1.1–2.6)***
| Telephone interview of mothers Age <15 years Matched for age, gender Adjusted for age. Gender, parental professional category, maternal age at the time of birth Maternal smoking was not associated with significant increased risk Trend analyses: *P < 0.0001 **P < 0.045 ***P < 0.01
| Low |
Schuz et al. (1999), Germany | Case control (NW and NI study) NW: 1992–97 NI: 1980–94
| 2354 cases 2588 controls 955 Acute leukaemia 955 controls 221 NHL 2540 controls
| Acute leukaemia and NHL Paternal smoking before pregnancy Acute leukaemia (ALL and AnLL) 1–10 CPD AOR 1.1 (0.8–1.5) 11–20 CPD AOR 1.0 (0.8–1.2) >20 CPD AOR 0.9 (0.7–1.2) NHL 1–10 CPD AOR 1.6 (1.0–2.5) 11–20 CPD AOR 1.1(0.7–1.6) >20 CPD AOR 1.1 (0.7–1.8)
| Questionnaire followed by telephone interview by parents Age <15years Matched for gender, age, region Adjusted for socio-economic status Not adjusted for maternal smoking, but no association with maternal smoking Study also includes estimates on CNS tumours, neuroblastoma, nephroblastoma, bone tumour, soft tissue sarcoma and no associations was found
| Medium |
Shu et al. (1996), USA | Case control 1983–88 (CCG study)
| 302 cases 203 ALL 88 AML 11 other leukaemia 558 controls Paternal smoking: 191 ALL 79 AML
| ALL and AML Only paternal smoking 1 month prior to pregnancy (A) and during pregnancy (B) A: ALL: AOR 1.56 (1.03–2.36) 1–10 CPD AOR 2.40 (1.00–5.72) 11–20 CPD AOR 1.33 (0.79–2.34) >20 CPD AOR 1.51 (0.82–2.77) AML: AOR 0.75 (0.35–1.62) 1–10 CPD AOR 0.42 (0.09–1.95) 11–20 CPD AOR 0.73 (0.27–1.94) >20 CPD AOR 1.29 (0.44–3.74) B: ALL: AOR 1.45 (0.95–2.19) AML: AOR 0.82 (0.38–1.78)
| Telephone interview with mothers and fathers (71%) Age ≤18 months Matched by age, region. Adjusted for sex, paternal age, education, maternal alcohol consumption during pregnancy Maternal smoking 1 month prior to pregnancy and during pregnancy was not associated with increased risk of ALL or AML
| Low |
Sorahan et al. (2001), UK | Case control (OSCC study) 1980–83
| 555 cases 555 controls (GP) Cases/controls: 7/9 18/16 36/35 9/5 12/3
| | Interview of parents Child age <15 years Matched on region, sex, date of birth Adjusted for maternal age, paternal age, SES, ethnicity
| Low |
Other cancers n = 19 |
Barrington-Trimis et al. (2013), USA | | 202 cases 286 controls Only paternal smoking: 25 cases 27 controls
| | In-person maternal interview Age ≤10 years Matched by age, sex, study centre Adjusted for race, sex, age at diagnosis, maternal education, birth year, centre
| Low |
Bunin et al. (1994), USA | Case control 1986–1989 | 155 AP 166 PNET 321 Controls 64/63 60/58 86/82 85/88
| | Trained interviewers with parents Child age <6 years Matched on race, year of birth, telephone area code and prefix AG: Adj. income level PNET: No adjustment
| Low |
Filippini et al. (2002), Italy | | 1218 cases 2223 controls 633/1190
| Brain tumours AOR 1.1 (0.9–1.2)
| Nine centres in 7 countries In-person interview of mostly mothers Child age 0–19 years Post hoc strata matched on age, sex and centre Adjusted for matched variables and maternal level of education
| Medium |
Gold et al. (1993), USA | | 361 cases 1083 controls Only paternal smoking: 81 cases 247 controls
| | Structured interview from each parent Age <18 years Matched for age, sex, maternal race Cases represent 85% of cases identified by the registries
| Medium |
Hu et al. (2000), China | | | Brain tumours Smoking PY AOR 1.16 (0.65–2.08)
| During hospitalization, paternal and maternal interviews by trained interviewers Age <19 years Matched for sex, age, area of residence Adjusted for maternal education, family income
| Low |
Ji et al. (1997), China | | 1981–91 642 cases 642 controls Brain tumours 107 pairs Acute leukaemia, 166 pairs Lymphoma 87 pairs
| Brain tumours Paternal smoking before conception <2 PY All cancers: AOR 1.2 (0-8-1.8) Brain tumours: AOR 1.5 (0.5–4.4) 2–5 PY All cancers: AOR 1.3 (0.9–2.0) Brain tumours: AOR 1.7 (0.5–5.8) >5 PY prior to conception All cancers: AOR 1.7 (1.2–2.5) Brain tumours: AOR 2.7 (0.8–9.9)
| Paternal and maternal interviews by trained interviewers Age <15 years Matched for sex, year of birth Adjusted for BW, income, paternal age, education and alcohol
| Low |
John et al. (1991), USA | | 1976–1983 223 cases 196 controls 60 exposed cancers 45 exposed controls
| Brain tumours Paternal smoking in preconception period in the absence of maternal smoking Brain tumours: AOR 1.6 (0.7–3.5) All cancers: AOR 1.2 (0.8–2.1)
| Personal interview Prenatal exposure Matched for age, sex, area Absence of maternal smoking: Adjusted for father’s education
| Low |
Johnson et al. (2013)USA | Case control 2000–2008 (Cases) 1994–2008 (controls)
| | | Maternal telephone interviews Age <6 years Matched for BW, gender, birth year and region Adjusted for BW, year of birth, sex, maternal race and education Not directly adjusted for maternal smoking had no influence and therefore not adjusted for
| Medium |
McCredie et al. (1994), Italy + Australia | Case control Population-based 1985–1989
| 82 cases 164 controls Ever smoking 23 cases, 28controls During pregnancy 41cases, 49controls
| | | Low |
Milne et al. (2013), Australia | Case control (Aus-CBT study) 2005–2010
| 302 cases 941 controls Preconception: 74 cases 222 controls During pregnancy 71 cases 202 controls
| Brain tumours Paternal smoking preconception AOR 0.99 (0.71–1.38) 1–14 CPD: AOR 1.31 (0.82–2.11) 15+ CPD: AOR 0.83 (0.55–1.24) Paternal smoking during pregnancy* AOR 1.04 (0.74–1.46) 1–14 CPD: AOR 1.30 (0.79–2.13) 15+ CPD: AOR 0.92 (0.61–1.38)
| Questionnaire to parents Age <15 years Matched for age, sex, state of residence Adjusted for matching variables, ethnicity, year of birth group, parental age, household income *Results shown are not adjusted for maternal smoking, but no association was found with maternal smoking Similar results when analysis was restricted to children whose other parent did not smoke (data not shown)
| Medium |
Norman et al. (1996), USA | Case control Population-based 1984–1991
| 540 cases 801 controls Ever smoked: 262 cases, 380 controls During pregnancy: 174 cases, 238 controls
| | In-person or telephone interviews of mothers and fathers (77%) Child age <20 years Matched on birth year, sex, age at diagnosis Adj. matching criteria + maternal race/ethnicity
| Medium |
Pang et al. (2003), UK | Case control (UKCCS) 1991–1996
| | Cancer Paternal smoking during the year before birth All cancers 1–19 CPD: AOR 1.11 (0.98–1.25) 20+ CPD: AOR 1.01 (0.90–1.12) CNS tumours 1–19 CPD: AOR 1.08 (0.85–1.38) 20+ CPD: AOR 1.03 (0.82–1.28)
| Personal interview with parents Age <15 years Matched for sex, age, region Adjusted for matching variables, parental age, deprivation score
| Medium |
Plichart et al. (2008), France | Case control (ESCALE study) 2003–2004
| | | Maternal telephone interview Age <15 years Matched for age, sex and number of children <15 years of age in the household Adjusted for age, gender No association between maternal smoking during pregnancy and CNS tumours.
| Low |
Sorahan et al. (1997a), UK | Case control (OSCC study) 1953–1955
| 1549 cases 1549 controls 655 cases, 618 controls
| | Interview parents, usually mothers (response rate 88%) Matched for sex, date of birth and region Adjusted for social class, parental age at birth, sib-ship position, obstetric radiography
| Medium |
Sorahan et al. (1997b), UK | Case control (OSCC study) 1971–1976
| 2587 cases 2587 controls 630 cases 573 controls
| Death of childhood cancer Paternal smoking at death of child, father only 14% of the cancers could be related to paternal smoking (all cancer and onset at all ages) ARR 1.29 (1.10–1.51)
| Interview of parents, usually mothers Child age <16 years Matched for sex, date of birth, region Adjusted for social class, parental age at birth, sib-ship position, obstetric radiography
| Medium |
Sorahan et al. (2001), UK | Case control (OSCC study) 1980–83
| 555 cases 555 controls (hospital) 555 controls (GP) Cases/GP/Hospital 26/34/27 79/60/70 114/122/121 23/32/48 28/21/40
| Childhood cancer Paternal smoking before the pregnancy ARR: <10 CPD: GP: 0.94 (0.53–1.66); Hospital: 0.92 (0.51–1.65) 10–19 CPD GP: 1.63 (1.10–2.41); Hospital: 1.06 (0.72–1.56) 20–29 CPD GP: 1.46 (1.05–2.03); Hospital: 1.11 (0.80–1.53) 30–39 CPD GP: 0.95 (0.52–1.73); Hospital: 0.45 (0.26–0.77) 40+ CPD GP: 1.77 (0.94–3.34); Hospital: 0.66 (0.39–1.11) P for trend GP P = 0.02; Hospital P = 0.16 CNS tumours also stratified on CPD, but no total ARR P for trend 0.67 Data adjusted for maternal smoking is not shown but with a significant positive trend (P = 0.03) between cancer and paternal smoking compared to GP controls
| Interview of parents Child age <15 years Matched on region, sex, date of birth Adjusted for maternal age, paternal age, SES, ethnicity
| Low |
Sorahan and Lancashire (2004), UK | Case control (OSCC study) Deaths 1953–55 1971–76 1977–81
| | | Interview parents, usually mother Child age <16 years Matched for sex, age at death, year of death Adjusted for sex, age at death, year of death, social class, sib-ship position, maternal age, paternal age, obstetric radiography
| Medium (all cancers) Low (hepatoblastoma)
|
Schuz et al. (1999), Germany | Case control (NW and NI study) NW:1992–97 NI:1980–94
| NW:1992–97 NI:1980–94 2358 cases 2588 controls 385 CNS tumours 155 neuroblastomas 2540 nephroblastomas 95 bone tumours 133 soft tissue sarcomas
| CNS tumour, Neuroblastoma, Nephroblastoma, Bone tumour, Soft tissue sarcoma Paternal smoking before pregnancy 1-10 CPD: CNS tumour: AOR 0.8 (0.5–1.2) Neuroblastoma: AOR 0.6 (0.3–1.1) Nephroblastoma: AOR 0.8 (0.4–1.4) Bone tumour: AOR 0.5 (0.2–1.2) Soft tissue sarcoma: AOR 0.8 (0.4–1.6) 11–20 CPD: CNS tumour: AOR 1.1 (0.8–1.4) Neuroblastoma: AOR 1.1 (0.7–1.6) Nephroblastoma: AOR 0.8 (0.5–1.3) Bone tumour: AOR 0.8 (0.4–1.3) Soft tissue sarcoma: AOR 1.2 (0.8–1.8) >20CPD CNS tumour: AOR 1.0 (0.7–1.4) Neuroblastoma: AOR 1.2 (0.7–2.1) Nephroblastoma: AOR 0.9 (0.5–1.6) Bone tumour: AOR 0.9 (0.4–1.8) Soft tissue sarcoma: AOR 0.9 (0.4–1.6)
| Questionnaire followed by telephone interview by parents Age <15years Matched for gender, age, region Adjusted for socio-economic status Not adjusted for maternal smoking, but no association with maternal smoking. Study also includes estimates on Acute leukaemia and NHL
| Low |
Yang et al. (2000), USA & Canada | Case control (CCG and POG studies) 1992–94
| 504 cases 504 controls Preconception 137 cases, 122 controls
| | Telephone interview with parents Child age <19 years Matched for date of birth Adjusted for gender, mother’s race, father’s education, household income in birth year Not directly adjusted maternal smoking, but no association with risk of neuroblastoma
| Medium |
Cardio-metabolic outcomes (n = 9) |
Brion et al. (2007), UK | Cohort study Avon longitudinal study
| 6396 children (Model 1) 3736 children (Model 5)
| Blood pressure at 7 years Systolic blood pressure: Model 1: Beta 0.44 (−0.07–0.95) P = 0.09 Model 5: Beta 0.17 (−0.52–0.86) P = 0.6 Diastolic blood pressure: Model 1: Beta 0.10 (−0.26–0.47) P = 0.6 Model 5: Beta −0.25 (−0.72–0.22) P = 0.3
| Questionnaires sent to partners at 18 weeks gestation on if they had smoked regularly in the last 9 months Model 1: Child age, sex Model 5: Additionally, adjusted for maternal/partner factors, social factors, breast feeding
| Medium |
de Jonge et al. (2013), US | | 5777 non-smoking mothers 3078 paternal smoking 2699 no paternal smoking
| Hypertension in daughters in adulthood (self-reported physician diagnosed) Paternal smoking during pregnancy Maternal age: ARR 1.12 (1.06–1.18) + perinatal variables: ARR 1.09 (1.03–1.15) + BW: ARR 1.08 (1.03–1.14) + adult life variables: ARR 1.08 (1.02–1.14) + body shape and weight until age: ARR 18:1.07 (1.01–1.13) + current BMI: 1.04 (0.99–1.10)
| Self-administered questionnaires to nurse’s mothers 2001 Cox proportion hazard models Multiple adj. and additional adj. for perinatal variables, adult life variables, body shape and weight until age 18 years, current BMI
| Medium |
Durmus et al. (2011), The Netherlands | Prospective cohort study 2002–2006
| | BMI at 3, 6, 12, 24, 36, 48 months Paternal smoking during pregnancy and difference in BMI at 12 months: Standardized coefficients (95% CI): 0.06 (−0.01, 0.13) 0–4 CPD 0.04 (−0.05, 0.13) ≥5 CPD 0.08 (−0.01, 0.17) P for trend P = 0.01 Similar no difference in BMI at 3, 6, 24, 36 and 48 months and no trend
| Postal questionnaires to mothers Linear mixed models Adj. Child’s age at visit, sex, paternal ethnicity and education, paternal height and weight and breast feeding (yes/no) Reporting bias Similar information completed by the fathers in 3358 participants – good agreement between mat and pat assessment
| Medium |
Florath et al. (2014), Germany | Prospective cohort Born 2000–2001
| | | During hospitalization after delivery standardized maternal interviews by trained interviewers. Follow-up to age 8 years Linear regression Adjusted for paternal BMI and education, maternal pre-pregnancy BMI, BW, monthly weight gain, exclusive breast feeding, body height, TV consumption, sports activities, diet score at 8 years and age at anthropometric measurements. Conclusion: Residual confounding conditions in smoking families by living rather than specific intrauterine exposure may account for the increased risk of offspring overweight
| Medium |
Howe et al. (2012), UK | Cohort study Avon longitudinal study
| Height: 4832 children PI: 4777 children BMI: 4534 children
| Growth 29–120 months Girls: 0.0012 (0.0021), P = 0.01 Boys: −0.0012 (0.0020), P = 0.8 Ponderal index 2–24 months: Girls: 0.0043 (0.0078), P = 0.35 Boys: −0.0011 (0.0069), P = 0.73 BMI 103–120 months: Girls: 0.0042 (0.0036), P = 0.54 Boys: 0.0033 (0.0021), P = 0.77
| Self-reported data Height 0–10 years Ponderal index 0–2 years BMI 2–10 years Maternal education, household social class, parity, maternal age, maternal height, maternal BMI, gestational age, breast feeding
| Medium |
Kwok et al. (2010), Hong Kong | Birth Cohort study 1997 | | BMI and height at child age 7 and 11 years Daily prenatal and early postnatal paternal smoking: BMI, Z-score difference, mean (95%CI) Child age 7 years: 0.10 (0.02–0.19) Child age 11 years: 0.16 (0.07–0.26) No difference in height Z scores
| Standardized self- administered questionnaire at maternal and child-health centres Daily prenatal and early postnatal paternal smoking in non-smoking women Adjusted for gender, birth order, highest parental education, mother’s place of birth, pubertal status (for 11 years) highest parental occupation, household income per person, breast feeding history, number of hospital admissions attributable to infections at 0 to 6 months
| Medium |
Leary et al. (2006), UK | Cohort study Avon longitudinal study
| Examination at 9 years 6470 children 5615 children* 3649 children**
| BMI, total fat, truncal fat, total lean (DXA scanner) at mean child age 9.9 years Paternal smoking during pregnancy *BMI: beta 0.11 (0.05, 0.17) < 0.001 *Total fat: beta 0.08 (0.03–0.13) P = 0.001
| Questionnaires to mothers Adjusted for maternal smoking *Sex, child age at DXA-scan, **Additionally adjusted for maternal, partner, social and infant feeding factors
| Medium |
Taal et al. (2013), The Netherlands | Prospective cohort study 2008–2012
| | Stroke, volume, cardiac output, larger AOD (aortic root diameter), fractional shortening at child age 6 years Regression coefficients Mean Systolic blood pressure (mmHg) −0.18 (−0.69–0.33) test for trend over smoking cat. 0.741 Mean diastolic blood pressure (mmHg) 0.12 (−0.39–0.52) test for trend over smoking cat. 0.702 Aortic root diameter (mm) Difference 0.17 (0.05–0.28)
| Questionnaires in second and third trimester Mixed models and multiple linear regression models Adjusted for maternal age, parity, mixed educational level, pre-pregnancy BMI, BP at intake, sex, GA, BW, breast feeding status, current age and BMI
| Medium |
Toschke et al. (2007), UK | Cohort study NCDS: 1958 BCS70:1970
| Two birth cohorts Total: 11 282 children NCDS: 5214 children BCS70: 6068 children
| Diabetes Mellitus Type 1 Paternal smoking OR 0.48 (0.29–0.80) Combined OR: AOR 0.44 (0.25–0.75) NCDS: AOR 0.37 (0.18–0.75) BCS70: AOR 0.54 (0.24–1.27)
| Interview of mothers NCDS: Up 16 years BCS70:5 and 10 years Adjusted for maternal smoking, sex, maternal age, paternal age, number of sibling, social class, cohort (NCDS, BCS70)
| Medium |
Neuro-developmental n = 6 |
Brion et al. (2010), UK | | | Psychological problems Paternal smoking during pregnancy Hyperactivity/attention problem** ALSPAC AOR 1.03 (0.91–1.17) Pelotas AOR 1.04 (0.71–1.50) Emotional/Internalizing problem** ALSPAC AOR 0.93 (0.82–1.06) Pelotas AOR 0.85 (0.58–1.24) Conduct/Externalizing problems** ALSPAC AOR 1.11 (0.98–1.26) Pelotas AOR 0.96 (0.66–1.41) Peer/social problems** ALSPAC AOR 1.01 (0.89–1.15) Pelotas AOR 0.98 (0.67–1.45)
| Unadjusted Maternal and paternal education, income, social class Mediators Parental psychological **Mutually adj. model incl. maternal and paternal smoking with adjustment for one another
| Medium (ALSPAC)Low (Pelotas) |
Langley et al. (2012), UK | | Fathers only smoking 6478 children ADHD diagnosis 5719 children
| ADHD Paternal smoking during pregnancy 0, 1–9, 10–19, >=20 cig per day Paternal smoking and mother non-smoking Adjusted beta=0.12 (0.04–0.20) AOR 1.42 (1.04–1.93)
| Self-reported questionnaire (mother) Child age 7–8 years Linear regression F-statistics Adjusted for sex, ethnicity, multiple pregnancy, maternal alcohol during, education, pregnancy, parental social class, maternal education
| Medium |
Nomura et al. (2010), USA | Cohort study | 209 children Fathers only smoking 40
| ADHD AOR 0.31 (0.06–1.92) ODD Not estimable ADHD and ODD AOR 0.85 (0.13–5.55)
| Interview of parents Age 3–4 years Adjusted for gender, age, race and BW of the child, maternal drinking during pregnancy, family SES, mother’s ADHD symptoms, father’s ADHD symptoms, mother and father’s smoking history
| Low |
Tang (2006), Hong Kong | | | | Self-administered questionnaire parents mostly mothers Age 2–3 years Matched for age and region Adjusted for environmental tobacco smoke (ETS) due to other household smoking other than paternal smoking, child sex, BW, breast feeding history, housing type, parents educational level and occupation
| Medium |
Tiesler et al. (2011), Germany | Cohort study Delivery 1997–1999
| | Behavioural problems Prenatal paternal smoking and environmental tobacco smoking (persons other than mothers smoking at home, ETS) Total difficult score (5/40) APOR 1.21 (0.45–3.27) Hyperactivity/inattention (8/40) APOR 2.03 (0.86–4.81)
| Self-administered questionnaires mothers 10 years follow-up Adjusted for sex, study centre, parental education, maternal age at birth, time in front of screen, single mother/father
| Low |
Zhu et al. (2014), Denmark | | 50 870 mothers participated in 7-years questionnaire 14 004 singletons with paternal smoking only 360 (2.6%) singletons with ADHD Both non-smokers ADHD: 892/49 072 (1.8%)
| | Questionnaire during pregnancy and at follow-up 7- years of age (mother) Cox regression adjusted for maternal age, parity, alcohol, SES, psychopathology, sex, diagnosis, education (registry)
| Medium |
Conclusion: Paternal smoking during pregnancy may be associated with a modest increase in cancer in offspring. Low certainty of evidence (GRADE⊕⊕○○).
Acute childhood leukaemia
Out of 19 original studies, two were of medium and 17 of low quality (Supplementary Table SIII, Table X). Studies rated as low quality included only a few cases, and the information on paternal smoking in the preconception period and during pregnancy was collected retrospectively from mothers several years after birth. The majority of studies found no association between maternal smoking and childhood leukaemia, hence they did not adjust for maternal smoking in the analyses of paternal smoking.
Acute lymphoblastic leukaemia
Two meta-analyses on paternal smoking and ALL have been published (Liu et al., 2011; Milne et al., 2012). Milne et al. (2012) included both a meta-analysis and original data in their paper (Table X). All 10 studies included in the meta-analysis by Milne et al. (2012) were also included in the meta-analysis by Liu et al. (2011), except for the original data: the latter meta-analysis included 18 case control studies. Thirteen studies explored paternal smoking during the preconception period (AOR 1.25, 95% CI 1.08–1.46) and eight studies during pregnancy (AOR 1.24, 95% CI 1.07–1.43). Their dose–response analysis estimated a higher risk associated with an increased number of cigarettes a day (CPD), >20 CPD (AOR 1.30; 95% CI 1.09–1.55) (Liu et al., 2011). Milne et al. (2012) also found a significantly increased risk of ALL when fathers smoked around the time of conception (AOR 1.15, 95% CI 1.06–1.24). For >20 CPD their meta-analysis included seven studies (AOR 1.44, 95% CI 1.24–1.68).
Three low quality studies out of the 17 original studies in this systematic review were not included in the meta-analysis. Castro-Jimenez and Orozco-Vargas (2011) included 85 matched pairs and found AOR 1.93 (95% CI 1.06–3.54), Farioli et al. (2014) included only risk estimates according to the following categories 1–10 CPD (AOR 0.86, 95% CI 0.58–1.26) and >10 CPD (AOR 0.74 (95% CI 0.51–1.05). The Metayer et al. (2013) study was an expansion of Chang’s (Chang et al., 2006) (included in both meta-analyses) and found an AOR 0.94 (95% CI 0.69–1.27). Based on the meta-analyses, paternal smoking was associated with a 15–25% increased risk of ALL.
Conclusion: Paternal smoking may be associated with a slightly higher risk of childhood ALL. Low certainty of evidence (GRADE⊕⊕○○).
Acute myeloid leukaemia
Twelve original studies (two of medium quality and 10 of low quality) evaluated the outcome of paternal smoking on acute myeloid leukaemia (AML) (Supplementary Table SIII, Table X). The meta-analysis included eight studies and two unpublished reports. Figures for paternal smoking prior to conception were AOR 1.19 (95% CI 1.00–1.41) and during pregnancy AOR 1.28 (95% CI 1.05–1.57). All original studies in our systematic review are included in the meta-analysis.
Conclusion: There appears to be little or no association between paternal smoking and childhood AML. Low certainty of evidence (GRADE⊕⊕○○).
Brain tumours
Fourteen studies explored the association between paternal smoking prior to and during pregnancy, and brain tumours (Supplementary Table SIII, Table X). All were included in our meta-analysis, which showed a significant association between paternal smoking and brain tumours (pooled estimate 1.12, 95% CI 1.03–1.22) (Fig. 19).
Figure 19
Forest plot describing the association between paternal smoking and risk for brain tumours in the offspring.
Conclusion: Paternal smoking may be associated with a small increase in childhood brain tumours. Low certainty of evidence (GRADE⊕⊕○○)
Cardio-metabolic outcomes
Nine cohort studies of medium quality assessed paternal smoking and cardio-metabolic outcomes in offspring (Supplementary Table SIII, Table X). Five studies examined BMI (Leary et al., 2006; Kwok et al., 2010; Durmus et al., 2011; Howe et al., 2012; Florath et al., 2014), three studies looked at blood pressure and hypertension (Brion et al., 2007; de Jonge et al., 2013; Taal et al., 2013), and one study explored DM type 1 (Toschke et al., 2007). Due to the heterogeneity of the studies, meta-analyses could not be performed for any of these outcomes.
The BMI of children was measured at various ages in the five studies and the results diverged. In two of the studies, no linear associations were observed between paternal smoking and BMI (Durmus et al., 2011; Howe et al., 2012). However, three studies showed a negative linear association between paternal smoking and BMI in children aged 7 to 10 years (Leary et al., 2006; Kwok et al., 2010; Florath et al., 2014).
Brion et al. (2007) and Taal et al. (2013) showed no association between paternal smoking and diastolic or systolic BP in offspring in the adjusted models, neither did de Jonge et al. (2013) show any association between paternal smoking and hypertension in daughters. Toschke et al. (2007), in two combined cohorts, showed significantly lower risk estimates of DM type 1 in children where fathers smoked during pregnancy (AOR 0.44, 95% CI 0.25–0.75).
Conclusion: It is uncertain whether there is any association between paternal smoking and BMI in offspring. Very low certainty of evidence (GRADE⊕○○○). There may be little or no association between paternal smoking and blood pressure in offspring. Low certainty of evidence (GRADE⊕⊕○○). It is uncertain whether there is any association between paternal smoking and DM type 1 in the offspring. Very low certainty of evidence (GRADE⊕○○○).
Neuro-developmental outcomes
Six cohort studies explored the association between paternal smoking and neuro-developmental outcomes, out of which three cohort studies studied ADHD (Nomura et al., 2010; Langley et al., 2012; Zhu et al., 2014) (Supplementary Table SIII, Table X). All studies were heterogeneous regarding child age, questionnaires used for the parents, and outcome measures. Two of the studies found a significant association between paternal smoking and ADHD (AOR ranging from 1.29–1.42) (Langley et al., 2012; Zhu et al., 2014), while Nomura et al. (2010) found no significantly increased risk (AOR 0.31, 95% CI 0.06–1.92). In Langley et al. (2012) and Zhu et al. (2014) the children were 7 and 8 years of age, while the children in Nomura et al. (2010) were only 3 and 4 years old. None of the other studies found any associations between paternal smoking and neuro-developmental outcomes, except Brion et al. (2010), who found a significant association between paternal smoking and conduct/externalizing problems (AOR 1.12, 95% CI 1.02–1.24).
Conclusion: Paternal smoking may be associated with a small increase in ADHD. Low certainty of evidence (GRADE⊕⊕○○). It is uncertain if there is any association between paternal smoking and other neuro-developmental outcomes. Very low certainty of evidence (GRADE⊕○○○).
Discussion
General discussion
In this systematic review and meta-analysis we have tried to summarize the evidence for the effect of paternal factors on perinatal and paediatric outcomes. Paternal factors investigated in the present paper were paternal age and life-style factors, in particular smoking and BMI/height/weight of the fathers at time of conception. Other exposures, such as male subfertility and teratogenic drugs, have not been included in the present systematic review. Table XI presents a summary of the findings from the meta-analyses.
Table XISummary results of the meta-analyses of the association between paternal factors and perinatal and paediatric outcomes.
Exposure
. | Outcome
. | Pooled estimate (with 95% CI)
. | Certainty of evidence GRADE
. |
---|
Paternal age | PTB | 1.02 (1.00–1.05) | ⊕⊕○○ |
Low BW | 1.00 (0.97–1.03) | ⊕⊕○○ |
Stillbirth | 1.19 (1.10–1.30) | ⊕⊕○○ |
Children with any birth defects | 1.05 (1.02–1.07) | ⊕⊕⊕○ |
CHDs | 1.03 (0.99–1.06) | ⊕⊕⊕○ |
Orofacial clefts | 0.99 (0.95–1.04) 1.14 (1.02–1.29)* | ⊕⊕○○ |
Gastroschisis | 0.88 (0.78–1.00) | ⊕⊕⊕○ |
Spina bifida | 0.97 (0.90–1.04) | ⊕⊕⊕○ |
Trisomy 21 | 1.13 (1.05–1.23) | ⊕⊕⊕○ |
Acute lymphoblastic leukaemia | 1.08 (0.96–1.21) | ⊕⊕⊕○ |
Autism and ASDs | 1.25 (1.20–1.30) | ⊕⊕⊕○ |
Schizophrenia | 1.31 (1.23–1.38) | ⊕⊕⊕○ |
Paternal BMI | No meta-analysis |
Paternal smoking | PTB | 1.16 (1.00–1.35) | ⊕⊕○○ |
Low BW | 1.10 (1.00–1.21) | ⊕⊕○○ |
SGA | 1.22 (1.03–1.44) | ⊕⊕○○ |
CHDs | 1.75 (1.25–2.44) | ⊕⊕○○ |
Orofacial clefts | 1.51 (1.16–1.97) | ⊕⊕○○ |
Brain tumours | 1.12 (1.03–1.22) | ⊕⊕○○ |
Exposure
. | Outcome
. | Pooled estimate (with 95% CI)
. | Certainty of evidence GRADE
. |
---|
Paternal age | PTB | 1.02 (1.00–1.05) | ⊕⊕○○ |
Low BW | 1.00 (0.97–1.03) | ⊕⊕○○ |
Stillbirth | 1.19 (1.10–1.30) | ⊕⊕○○ |
Children with any birth defects | 1.05 (1.02–1.07) | ⊕⊕⊕○ |
CHDs | 1.03 (0.99–1.06) | ⊕⊕⊕○ |
Orofacial clefts | 0.99 (0.95–1.04) 1.14 (1.02–1.29)* | ⊕⊕○○ |
Gastroschisis | 0.88 (0.78–1.00) | ⊕⊕⊕○ |
Spina bifida | 0.97 (0.90–1.04) | ⊕⊕⊕○ |
Trisomy 21 | 1.13 (1.05–1.23) | ⊕⊕⊕○ |
Acute lymphoblastic leukaemia | 1.08 (0.96–1.21) | ⊕⊕⊕○ |
Autism and ASDs | 1.25 (1.20–1.30) | ⊕⊕⊕○ |
Schizophrenia | 1.31 (1.23–1.38) | ⊕⊕⊕○ |
Paternal BMI | No meta-analysis |
Paternal smoking | PTB | 1.16 (1.00–1.35) | ⊕⊕○○ |
Low BW | 1.10 (1.00–1.21) | ⊕⊕○○ |
SGA | 1.22 (1.03–1.44) | ⊕⊕○○ |
CHDs | 1.75 (1.25–2.44) | ⊕⊕○○ |
Orofacial clefts | 1.51 (1.16–1.97) | ⊕⊕○○ |
Brain tumours | 1.12 (1.03–1.22) | ⊕⊕○○ |
Table XISummary results of the meta-analyses of the association between paternal factors and perinatal and paediatric outcomes.
Exposure
. | Outcome
. | Pooled estimate (with 95% CI)
. | Certainty of evidence GRADE
. |
---|
Paternal age | PTB | 1.02 (1.00–1.05) | ⊕⊕○○ |
Low BW | 1.00 (0.97–1.03) | ⊕⊕○○ |
Stillbirth | 1.19 (1.10–1.30) | ⊕⊕○○ |
Children with any birth defects | 1.05 (1.02–1.07) | ⊕⊕⊕○ |
CHDs | 1.03 (0.99–1.06) | ⊕⊕⊕○ |
Orofacial clefts | 0.99 (0.95–1.04) 1.14 (1.02–1.29)* | ⊕⊕○○ |
Gastroschisis | 0.88 (0.78–1.00) | ⊕⊕⊕○ |
Spina bifida | 0.97 (0.90–1.04) | ⊕⊕⊕○ |
Trisomy 21 | 1.13 (1.05–1.23) | ⊕⊕⊕○ |
Acute lymphoblastic leukaemia | 1.08 (0.96–1.21) | ⊕⊕⊕○ |
Autism and ASDs | 1.25 (1.20–1.30) | ⊕⊕⊕○ |
Schizophrenia | 1.31 (1.23–1.38) | ⊕⊕⊕○ |
Paternal BMI | No meta-analysis |
Paternal smoking | PTB | 1.16 (1.00–1.35) | ⊕⊕○○ |
Low BW | 1.10 (1.00–1.21) | ⊕⊕○○ |
SGA | 1.22 (1.03–1.44) | ⊕⊕○○ |
CHDs | 1.75 (1.25–2.44) | ⊕⊕○○ |
Orofacial clefts | 1.51 (1.16–1.97) | ⊕⊕○○ |
Brain tumours | 1.12 (1.03–1.22) | ⊕⊕○○ |
Exposure
. | Outcome
. | Pooled estimate (with 95% CI)
. | Certainty of evidence GRADE
. |
---|
Paternal age | PTB | 1.02 (1.00–1.05) | ⊕⊕○○ |
Low BW | 1.00 (0.97–1.03) | ⊕⊕○○ |
Stillbirth | 1.19 (1.10–1.30) | ⊕⊕○○ |
Children with any birth defects | 1.05 (1.02–1.07) | ⊕⊕⊕○ |
CHDs | 1.03 (0.99–1.06) | ⊕⊕⊕○ |
Orofacial clefts | 0.99 (0.95–1.04) 1.14 (1.02–1.29)* | ⊕⊕○○ |
Gastroschisis | 0.88 (0.78–1.00) | ⊕⊕⊕○ |
Spina bifida | 0.97 (0.90–1.04) | ⊕⊕⊕○ |
Trisomy 21 | 1.13 (1.05–1.23) | ⊕⊕⊕○ |
Acute lymphoblastic leukaemia | 1.08 (0.96–1.21) | ⊕⊕⊕○ |
Autism and ASDs | 1.25 (1.20–1.30) | ⊕⊕⊕○ |
Schizophrenia | 1.31 (1.23–1.38) | ⊕⊕⊕○ |
Paternal BMI | No meta-analysis |
Paternal smoking | PTB | 1.16 (1.00–1.35) | ⊕⊕○○ |
Low BW | 1.10 (1.00–1.21) | ⊕⊕○○ |
SGA | 1.22 (1.03–1.44) | ⊕⊕○○ |
CHDs | 1.75 (1.25–2.44) | ⊕⊕○○ |
Orofacial clefts | 1.51 (1.16–1.97) | ⊕⊕○○ |
Brain tumours | 1.12 (1.03–1.22) | ⊕⊕○○ |
The systematic literature search revealed a huge number of articles which were scrutinized, and 238 of these publications were selected for inclusion. Although the quality of included articles varied, several large cohort studies of high quality were identified.
A majority of the included publications investigated the effect of paternal age on the health of children. A previous systematic review concerning the effect of paternal factors on obstetric outcomes found that extremes in paternal age were associated with an increase in LBW, and there was also an association between paternal height and BW of offspring (Shah, 2010). Another recent report summarized the association between paternal age and health of offspring in a narrative way (Nybo Andersen and Urhoj, 2017). They reported a strong association between paternal age and some specific congenital syndromes, namely cleft palate, acute lymphatic leukaemia, ASD and schizophrenia.
While no clear definition seems to exist for advanced paternal age, many studies have used 40 years and above as an age limit. A common problem for many studies of paternal factors, particularly paternal age, is the strong and well-known confounding factor, namely the effect of maternal age on obstetric and child outcome. A similar influence is true for other exposures, such as smoking and BMI. In our meta-analyses we therefore only included publications which had adjusted for maternal age or smoking, or where it was clear that the reference group was young mothers or non-smoking mothers, respectively. We also included some studies in which univariate analysis of maternal smoking was insignificant, and thus did not adjust for maternal smoking in the multivariate analyses.
Paternal age
Among obstetric outcomes, we found a small but significantly increased risk of stillbirth associated with paternal age. We also found significantly higher risks of birth defects, and specifically of orofacial clefts and trisomy 21. For other obstetric outcomes and selected birth defects we could not identify any increased risks. For gastroschisis, there seems to be evidence of an increased risk associated with younger fathers (Kazaura et al., 2004a, Archer et al., 2007, Yang et al., 2007, Materna-Kiryluk et al., 2009). The mechanism behind such an association is suggested to be of socio-economic origin, with certain life-style factors more common among young fathers (drugs, smoking, etc) while the increase in risk associated with higher paternal age is possibly of genetic origin, depending on a higher frequency of de novo mutation in sperm of older fathers.
Children born to older fathers have been reported as having a higher risk of various cancer types (Sartorius and Nieschlag, 2010). A meta-analysis (Sergentanis et al., 2015) reported an increased risk of childhood leukaemia associated with higher parental ages. For the risk of ALL, they reported an association with both increased maternal and paternal age. In our meta-analysis we did not find an association between ALL and advanced paternal age. A possible explanation for our result could be that we only included studies that adjusted for maternal age. For other cancer types, it was not possible to carry out meta-analysis, either because the studies were too few, of too low quality, or did not adjust for maternal age.
Psychiatric disorders and diseases like autism/ASD (Hultman et al., 2011; Wu et al., 2017) and schizophrenia (Miller et al., 2010) have been associated with advanced paternal age. From earlier studies, the risk seems to increase linearly without any particular threshold. This link with advanced paternal age has been found in studies from different countries although the magnitude of the associations varies.
ASD is a chronic disease and includes different conditions such as infantile autism, Asperger’s syndrome, atypical autism and pervasive development disorder. There are different theories explaining the aetiology. The genetics of ASD seem complex and may involve genetic, epigenetic and environmental factors (Waye and Cheng, 2017). The mean number of de novo mutations in human spermatozoa has been found to increase by around two per year (Kong et al., 2012). This increased frequency of de novo mutations of older men may result in both gain and loss of DNA region copy numbers, and may explain some of the effects associated with increased paternal age. Other explanations for the paternal effects may include the fact that these men are more often in the higher or lower socio-economic groups, they are more likely to be overweight and obese, and they are more likely to smoke and have a higher alcohol intake. Furthermore, these men more often suffer from diverse physical and mental health problems (Nilsen et al., 2013).
In our meta-analysis of autism, 16 studies were included and a higher risk of autism/ASD was associated with increasing paternal age (pooled estimate 1.25, 95% CI 1.20–1.30). All studies adjusted for maternal age. This finding is in line with previous meta-analyses (Hultman et al., 2011; Wu et al., 2017).
Our meta-analysis of schizophrenia included 11 original articles, all of these studies adjusted for maternal age. A higher risk of schizophrenia was observed in the children of older men (pooled estimate 1.31, 95% CI 1.24–1.38). The previous meta-analysis by Miller et al. (2010) found a higher level of risk in the oldest fathers (≥50 years), of AOR 1.66 (95% CI 1.46–1.89). Similarly, the meta-analyses by Torrey et al. (2009) and Wohl and Gorwood (2007) found a strong association between advanced paternal age and an increased risk of schizophrenia in offspring. Limitations in some of the studies include few outcomes of interest, and poorly defined classification of diagnosis. Another limitation is that it is not possible to adjust for genetic and environmental factors that could be important confounders in the association between advanced paternal age and adverse outcomes in offspring. Furthermore, there is a heterogeneity of different age categories that complicates comparison between studies. Our results are in line with previous studies and indicate an association between advanced paternal age and increased risk of autism, schizophrenia and other psychiatric diseases.
Paternal, BMI, height and/or weight
There are only limited data on the impact of paternal obesity at the time of conception on short and long-term health outcomes for children. Information on the father´s weight and BMI was often documented after the birth of the child, and those studies were excluded from the analysis. Paternal obesity has been connected to infertility, a reduced rate of live birth per cycle in ART, and increased risk of pregnancy non-viability (Campbell et al., 2015). Obese men have an increased amount of sperm with low mitochondrial membrane potential, DNA fragmentation, and abnormal morphology, all of which may have harmful effects on fertility (Campbell et al., 2015). However, if the pregnancy starts, pre-pregnancy paternal BMI does not seem to exert any independent effect on the risk of PTB or SGA (Mutsaerts et al., 2014). Actually, with regard to short-term outcomes, only the height of the father correlated significantly with the BW of the offspring. On the other hand, paternal anthropometrics at the time of the child’s birth were associated with childhood BMI, weight and/or fat mass. However, paternal height and weight were usually either self-reported, or reported by the mother, and not measured, which increases the risk of bias. The majority of studies reported a stronger effect of maternal BMI than paternal BMI. In one study, Patro and co-workers systematically evaluated the associations of offspring BMI, or adiposity, with pre-pregnancy BMI (or adiposity) of the mother and the father (Patro et al., 2013). They hypothesized that the intrauterine environment is an independent factor in obesity development, and thus the maternal effect is likely to be stronger (‘foetal overnutrition hypothesis’), but found only limited evidence to support the hypothesis.
Paternal smoking
Our meta-analyses on short-term outcomes demonstrated a small but significant increased risk of SGA if fathers smoked, but non-significant increased risks of PTB and LBW. While the effect of maternal smoking on obstetric outcomes is evident, the effect of paternal smoking on obstetric outcomes is still equivocal. Paternal smoking significantly increased CHD and orofacial clefts, with pooled estimates of 1.75 and 1.50 respectively. The occurrence of CHD and orofacial clefts is a result of the interaction of genetic and environmental risk factors and cigarette smoke comprises numerous chemical carcinogens. These chemicals have a teratogenic effect on oocytes and sperm DNA or interfere with foetal cardiac development and other foetal structures (Deng et al., 2013; Figueiredo et al., 2015). The existing literature is not able to clarify if the increased risk of CHD associated with paternal smoking is due to a direct effect on sperm, or the result of passive smoking on oocytes or the foetus: an effect of the latter should be weaker than that of maternal smoking. The effect of maternal smoking on orofacial cleft risk is relatively well demonstrated, but an effect on cardiovascular defects is more dubious or perhaps restricted to only some forms. Thus, the effect of paternal smoking on orofacial clefts may be due to maternal passive smoking, and why the effect on CHD is more likely to be due to paternal smoking per se. Our meta-analysis of data on brain tumours showed a small but significant increased risk of brain tumours if fathers smoked, with pooled estimate of 1.12. The previous meta-analyses on data on leukaemia demonstrated an association between paternal smoking at pregnancy for AML (AOR 1.19–1.28) and for ALL (1.15–1.25) (Liu et al., 2011; Milne et al., 2012; Metayer et al., 2016). Tobacco smoke is known to be leukomogenic, to introduce oxidative damage in sperm cells resulting in DNA fragmentation, and it may also cause persistent changes in miRNA (Liu et al., 2011; Milne et al., 2012).
The association between paternal smoking and childhood cancer could hardly be due to maternal passive smoking as maternal smoking is not with certainty associated with childhood cancer. However, if the infant or young child has been exposed for passive smoking that may explain the increased cancer risk, if passive smoking has a carcinogenic effect. Most of the studies on the effects of exposure to paternal smoking during pregnancy had matched control groups, and risk estimates were adjusted for relevant confounding factors. Nevertheless, none of the studies were assessed as being of high quality. Most studies were retrospective case control studies with a limited number of cases and controls, where fathers but not mothers smoked.
In the majority of studies, the information on paternal smoking was gained from interviews with, or questionnaires from, the mothers, thus introducing recall and selection bias. Obviously, recall bias is of most concern in long-term outcomes where information on paternal smoking is obtained several years after childbirth. The extent of under reporting of paternal smoking is unknown, which may introduce some non-differential misclassification bias. Furthermore, the dissemination of information on the adverse consequences of smoking in pregnancy may have discouraged some parents from disclosing it. Even in some studies of short-term outcomes, information on BW and gestational age came in the form of maternal self-reported data rather than hospital files or national registries, meaning that accuracy is less certain. Most studies of long-term outcomes involved univariate analyses of maternal smoking, and if not significant, the final results were not adjusted for maternal smoking. Further differentiation between the impact on long-term outcomes of paternal smoking in the preconception stage, and during and after pregnancy, is a challenge. Exposure of pregnant women to tobacco smoke in the environment may be a confounding factor and likewise, second-hand smoke after delivery is a confounder when examining long-term outcomes.
Strengths and limitations
The major strength of this systematic review is the comprehensive literature search, identifying a huge number of relevant publications, from the beginning of the 1950s up to 2017. Another strength is the fact that it is possible to perform meta-analyses, making interpretation of the summarized literature much easier for the reader. The main limitation is the heterogeneity within the meta-analyses e.g. differences in paternal age groups, reference groups, outcome measures and statistical methods used in the studies included. This heterogeneity may, however, be of less importance since this systematic review/meta-analysis is based solely on observational studies and not on interventional trials. All estimates are thus limited to associations. Another limitation which has to be observed is that most of the estimates and 95% CI for the estimates are close to 1.00. Despite adjusting for confounders, for example maternal age, residual confounders might well exist, which could explain the association between paternal age and several of the outcomes.
Conclusion
This systematic review and meta-analysis investigating paternal age, smoking and BMI/weight/height as risk factors for adverse outcome in offspring, found elevated risks for selected birth defects and psychiatric disorders as well as for selected cancers and metabolic disturbances. Although these risks represent serious health effects for the children, the magnitude of these effects seems modest.
Supplementary data
Supplementary data are available at Human Reproduction Update online.
Acknowledgements
We thank Therese Svanberg, librarian at Sahlgrenska University Hospital, Sweden, for performing the literature search, Annette Nattland for secretary assistance and Gwyneth Olofsson for language correction.
Authors' roles
A.L., A.P., C.B., H.L., L.B.R., N.B.O., U.B.W. and V.S.A. contributed to the design of the study, screened articles, selected articles, performed data extraction, interpreted the data and wrote the manuscript. MP performed the statistical analyses. All authors approved the final version for submission.
Funding
The Nordic Expert group’s research work was unconditionally supported by Gedeon Richter Nordics in Finland, Norway and Denmark and by an agreement concerning research and the education of doctors in Gothenburg, Sweden (ALFGBG-70 940). V.S.A. was supported by a personal grant from the medical society ‘Life and Health’ in Finland.
Conflict of interest
None of the authors has any conflicts of interest to declare.
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